Imidazonaphthyridines

ABSTRACT

Imidazonaphthyridine and tetrahydroimidazonaphthyridine compounds induce the biosynthesis of cytokines such as interferon and tumor necrosis factor. The compounds exhibit antiviral and antitumor properties. Methods of preparing the compounds and intermediates useful in the preparation of the compounds are also disclosed.

FIELD OF THE INVENTION

[0001] This invention relates to imidazonaphthyridine andtetrahydroimidazonaphthyridine compounds, processes for making thesecompounds and intermediates used in their preparation. This inventionadditionally relates to pharmaceutical compositions containingimidazonaphthyridine and tetrahydroimidazonaphthyridine compounds. Afurther aspect of this invention relates to the use of these compoundsas immunomodulators and for inducing cytokine biosynthesis in animals.

BACKGROUND OF THE INVENTION

[0002] The first reliable report on the 1H-imidazo[4,5-c]quinoline ringsystem, Backman et al., J. Org. Chem. 15, 1278-1284 (1950) describes thesynthesis of1-(6-methoxy-8-quinolinyl)-2-methyl-1H-imidazo[4,5-c]quinoline forpossible use as an antimalarial agent. Subsequently, syntheses ofvarious substituted 1H-imidazo[4,5-c]quinolines were reported. Forexample, Jain et al., J. Med. Chem. 11, pp. 87-92 (1968), synthesizedthe compound 1-[2-(4-piperidyl)ethyl]-1H-imidazo[4,5-c]quinoline as apossible anticonvulsant and cardiovascular agent. Also, Baranov et al.,Chem. Abs. 85, 94362 (1976), have reported several2-oxoimidazo[4,5-c]quinolines, and Berenyi et al., J. Heterocyclic Chem.18, 1537-1540 (1981), have reported certain2-oxoimidazo[4,5-c]quinolines.

[0003] Certain 1H-imidazo[4,5-c]quinolin-4-amines and 1- and2-substituted derivatives thereof were later found to be useful asantiviral agents, bronchodilators and immunomodulators. These aredescribed in, inter alia, U.S. Pat. Nos. 4,689,338; 4,698,348;4,929,624; 5,037,986; 5,268,376; 5,346,905; and 5,389,640, all of whichare incorporated herein by reference. Although there continues to beinterest in the imidazoquinoline ring system, as seen for example in WO98/30562, there is a continuing need for compounds that have the abilityto modulate the immune response, by induction of cytokine biosynthesisor other mechanisms.

SUMMARY OF THE INVENTION

[0004] We have found a new class of compounds that are useful ininducing cytokine biosynthesis in animals. Accordingly, this inventionprovides imidazonaphthyridine compounds of Formula I:

[0005] wherein A, R₁ and R₂ are as defined hereinafter.

[0006] The invention also provides tetrahydroimidazonaphthyridinecompounds of Formula II:

[0007] wherein B, R₁ and R₂ are as defined hereinafter.

[0008] The compounds of Formula I and Formula II are useful as immuneresponse modifiers due to their ability to induce cytokine biosynthesisand otherwise modulate the immune reponse when administered to animals.This ability makes the compounds useful in the treatment of a variety ofconditions, e.g. viral diseases and tumors that are responsive to suchchanges in the immune response.

[0009] The invention further provides pharmaceutial compositionscontaining a compound of Formula I or Formula II and methods of inducingcytokine biosynthesis in an animal and/or treating a viral infection inan animal by administering a compound of Formula I or Formula II to theanimal.

[0010] In addition, methods of synthesizing compounds of Formula I andFormula II, and intermediates useful in the synthesis of these compoundsare provided.

[0011] Further the invention provides a method of inducing interferonbiosynthesis in an animal comprising the step of administering to saidanimal a compound of Formula I or Formula II in an amount effective toinduce said interferon biosynthesis, and a method of treating a viralinfection in an animal comprising the step of administering to saidanimal a compound of Formula I or Formula II in an amount effective toinhibit the viral infection.

DETAILED DESCRIPTION OF THE INVENTION

[0012] As mentioned earlier, the invention provides compounds of FormulaI:

[0013] wherein

[0014] A is ═N—CR═CR—CR═; ═CR—N═CR—CR═; ═CR—CR═N—CR═; or ═CR—CR═CR—N═;

[0015] R₁ is selected from the group consisting of:

[0016] hydrogen;

[0017] C₁₋₂₀ alkyl or C₂₋₂₀ alkenyl that is unsubstituted or substitutedby one or more substituents selected from the group consisting of:

[0018] aryl;

[0019] heteroaryl;

[0020] heterocyclyl;

[0021] O—C₁₋₂₀ alkyl,

[0022] O—(C₁₋₂₀alkyl)₀₋₁-aryl;

[0023] O—(C₁₋₂₀alkyl)₀₋₁-heteroaryl;

[0024] O—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl;

[0025] C₁₋₂₀-alkoxycarbonyl;

[0026] S(O)₀₋₂—C₁₋₂₀ alkyl;

[0027] S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-aryl;

[0028] S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl;

[0029] S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl;

[0030] N(R₃)₂;

[0031] N₃;

[0032] oxo;

[0033] halogen;

[0034] NO₂;

[0035] OH; and

[0036] SH; and

[0037] —C₁₋₂₀ alkyl-NR₃-Q-X—R₄ or —C₂₋₂₀ alkenyl-NR₃-Q-X—R₄ wherein Q is—CO— or —SO₂—; X is a bond, —O— or —NR₃— and R₄ is aryl; heteroaryl;heterocyclyl; or —C₁₋₂₀ alkyl or C₂₋₂₀ alkenyl that is unsubstituted orsubstituted by one or more substituents selected from the groupconsisting of:

[0038] aryl;

[0039] heteroaryl;

[0040] heterocyclyl;

[0041] O—C₁₋₂₀ alkyl,

[0042] O—(C₁₋₂₀alkyl)₀₋₁-aryl;

[0043] O—(C₁₋₂₀alkyl)₀₋₁-heteroaryl;

[0044] O—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl;

[0045] C₁₋₂₀ alkoxycarbonyl;

[0046] S(O)₀₋₂—C₁₋₂₀ alkyl;

[0047] S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-aryl;

[0048] S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl;

[0049] S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl;

[0050] N(R₃)₂;

[0051] NR₃—CO—O—C₁₋₂₀alkyl;

[0052] N₃; oxo;

[0053] halogen;

[0054] NO₂;

[0055] OH; and

[0056] —SH; or R₄ is

[0057] wherein Y is —N— or —CR—;

[0058] R₂ is selected from the group consisting of:

[0059] hydrogen;

[0060] C₁₋₁₀ alkyl;

[0061] C₂₋₁₀ alkenyl;

[0062] aryl;

[0063] C₁₋₁₀ alkyl —O—C₁₋₁₀-alkyl;

[0064] C₁₋₁₀ alkyl-O—C₂₋₁₀ alkenyl; and

[0065] C₁₋₁₀ alkyl or C₂₋₁₀ alkenyl substituted by one or moresubstituents selected from the group consisting of:

[0066] OH;

[0067] halogen;

[0068] N(R₃)₂;

[0069] CO—N(R₃)₂;

[0070] CO—C₁₋₁₀ alkyl;

[0071] N₃;

[0072] aryl;

[0073] heteroaryl;

[0074] heterocyclyl;

[0075] CO-aryl; and

[0076] CO-heteroaryl;

[0077] each R₃ is independently selected from the group consisting ofhydrogen and C₁₋₁₀ alkyl; and

[0078] each R is independently selected from the group consisting ofhydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, halogen and trifluoromethyl,

[0079] or a pharmaceutically acceptable salt thereof.

[0080] This invention also provides compounds of Formula II

[0081] wherein

[0082] B is —NR—C(R)₂—C(R)₂—C(R)₂—; —C(R)₂—NR—C(R)₂—C(R)₂—;—C(R)₂—C(R)₂—NR—C(R)₂— or —C(R)₂—C(R)₂—C(R)₂—NR—;

[0083] R₁ is selected from the group consisting of:

[0084] hydrogen;

[0085] C₁₋₂₀ alkyl or C₂₋₂₀ alkenyl that is unsubstituted or substitutedby one or more substituents selected from the group consisting of:

[0086] -aryl;

[0087] heteroaryl;

[0088] heterocyclyl;

[0089] O—C₁₋₂₀ alkyl;

[0090] O—(C₁₋₂₀alkyl)₀₋₁-aryl;

[0091] O—(C₁₋₂₀alkyl)₀₋₁-heteroaryl;

[0092] O—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl;

[0093] C₁₋₂₀ alkoxycarbonyl;

[0094] S(O)₀₋₂—C₁₋₂₀ alkyl;

[0095] S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-aryl;

[0096] S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl;

[0097] S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl;

[0098] N(R₃)₂;

[0099] N₃;

[0100] oxo;

[0101] halogen;

[0102] NO₂;

[0103] OH; and

[0104] SH; and

[0105] C₁₋₂₀ alkyl-NR₃-Q-X—R₄ or —C₂₋₂₀ alkenyl-NR₃-Q-X—R₄ wherein Q is—CO— or —SO₂—; X is a bond, —O— or —NR₃— and R₄ is aryl; heteroaryl;heterocyclyl; or —C₁₋₂₀ alkyl or C₂₋₂₀ alkenyl that is unsubstituted orsubstituted by one or more substituents selected from the groupconsisting of:

[0106] aryl;

[0107] heteroaryl;

[0108] heterocyclyl;

[0109] O—C₁₋₂₀ alkyl,

[0110] O—(C₁₋₂₀alkyl)₀₋₁-aryl;

[0111] O—(C₁₋₂₀alkyl)₀₋₁-heteroaryl;

[0112] O—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl;

[0113] C₁₋₂₀ alkoxycarbonyl;

[0114] S(O)₀₋₂—C₁₋₂₀ alkyl;

[0115] S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-aryl;

[0116] S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl;

[0117] S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl;

[0118] N(R₃)₂;

[0119] NR₃—CO—O—C₁₋₂₀alkyl;

[0120] N₃;

[0121] oxo;

[0122] halogen;

[0123] NO₂;

[0124] OH; and

[0125] SH; or R₄ is

[0126] wherein Y is —N— or —CR—;

[0127] R₂ is selected from the group consisting of:

[0128] hydrogen;

[0129] C₁₋₁₀ alkyl;

[0130] C₂₋₁₀ alkenyl;

[0131] aryl

[0132] C₁₋₁₀ alkyl-O—C₁₋₁₀-alkyl;

[0133] C₁₋₁₀ alkyl-O—C₂₋₁₀alkenyl; and

[0134] C₁₋₁₀ alkyl or C₂₋₁₀ alkenyl substituted by one or moresubstituents selected from the group consisting of:

[0135] OH;

[0136] halogen;

[0137] N(R₃)₂;

[0138] CO—N(R₃)₂;

[0139] CO—C₁₋₁₀ alkyl;

[0140] N₃;

[0141] aryl;

[0142] heteroaryl;

[0143] heterocyclyl;

[0144] CO-aryl; and

[0145] CO-heteroaryl;

[0146] each R₃ is independently selected from the group consisting ofhydrogen and C₁₋₁₀ alkyl; and

[0147] each R is independently selected from the group consisting ofhydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, halogen and trifluoromethyl,

[0148] or a pharmaceutically acceptable salt thereof.

[0149] As used herein, the terms “alkyl”, “alkenyl”, and the prefix“-alk” are inclusive of both straight chain and branched chain groupsand of cyclic groups, i.e. cycloalkyl and cycloalkenyl. These cyclicgroups can be monocyclic or polycyclic and preferably have from 3 to 10ring carbon atoms. Exemplary cyclic groups include cyclopropyl,cyclopentyl, cyclohexyl and adamantyl.

[0150] The term “aryl” as used herein includes carbocyclic aromaticrings or ring systems. Examples of aryl groups include phenyl, naphthyl,biphenyl, fluorenyl and indenyl. The term “heteroaryl” includes aromaticrings or ring systems that contain at least one ring hetero atom (e.g.,O, S, N). Suitable heteroaryl groups include furyl, thienyl, pyridyl,quinolinyl, tetrazolyl, imidazo, and so on.

[0151] “Heterocyclyl” includes non-aromatic rings or ring systems thatcontain at least one ring hetero atom (e.g., O, S, N). Exemplaryheterocyclic groups include pyrrolidinyl, tetrahydrofuranyl,morpholinyl, thiazolidinyl, and imidazolidinyl.

[0152] The aryl, heteroaryl and heterocyclyl groups may be unsubstitutedor substituted by one or more substituents selected from the groupconsisting of C₁₋₂₀ alkyl, hydroxy, halogen, N(R₃)₂, NO₂, C₁₋₂₀ alkoxy,C₁₋₂₀ alkylthio, trihalomethyl, C₁₋₂₀ acyl, arylcarbonyl,heteroarylcarbonyl, (C₁₋₁₀alkyl)₀₋₁-aryl, (C₁₋₁₀alkyl)₀₋₁-heteroaryl,nitrile, C₁₋₂₀ alkoxycarbonyl, oxo, arylalkyl wherein the alkyl grouphas from 1 to 10 carbon atoms, and heteroarylalkyl wherein the alkylgroup has from 1 to 10 carbon atoms.

[0153] The invention is inclusive of the compounds described herein inany of their pharmaceutically acceptable forms, including isomers suchas diastereomers and enantiomers, salts, solvates, polymorphs, and thelike.

[0154] Preparation of the Compounds

[0155] Compounds of Formulas I and II wherein A is ═N—CR═CR—CR═ or B is—NR—C(R)₂—C(R)₂—C(R)₂— and R, R₁ and R₂ are as defined above can beprepared according to Reaction Scheme I:

[0156] Many 2-aminonicotinic acids of Formula III are known (see, forexample, U.S. Pat. No. 3,917,624). The compound where R is hydrogen iscommercially available. In step (1) of Reaction Scheme I a2-aminonicotinic acid of Formula III is reacted with acetic anhydride byheating to provide a 2-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one ofFormula IV. The compound of Formula IV where R is hydrogen is known andits preparation has been disclosed in U.S. Pat. No. 3,314,941 (Littell),the disclosure of which is incorporated herein by reference.

[0157] In step (2) of Reaction Scheme I a compound of Formula IV isreacted with sodium azide in a suitable solvent such as acetic acid toprovide a tetrazolyl nicotinic acid of Formula V. The reactionconveniently may be run at ambient conditions.

[0158] In step (3) of Reaction Scheme I an acid of Formula V isesterified to provide a compound of Formula VI. The esterification maybe carried out using conventional methods. For example, the acid may beesterified in acetone using potassium carbonate and ethyl iodide.

[0159] In step (4) of Reaction Scheme I a compound of Formula VI iscyclized to provide a tetrazolo[1,5-a][1,8]naphthyridin-5-ol of FormulaVII. The reaction may be carried out by reacting the compound of FormulaVI with an alkoxide in a suitable solvent, e.g., potassium ethoxide inN,N-dimethylformamide, at ambient conditions.

[0160] In step (5) of Reaction Scheme I a compound of Formula VII isnitrated using a suitable nitrating agent such as nitric acid to providea 4-nitrotetrazolo[1,5-a][1,8]naphthyridin-5-ol of Formula VIII.

[0161] In step (6) of Reaction Scheme I a compound of Formula VIII isconverted to a triflate of Formula IX. The reaction is preferablycarried out by combining a compound of Formula VIII with a base,preferably a tertiary amine such as triethyl amine, in a suitablesolvent such as dichloromethane and then adding trifluoromethanesulfonicanhydride. The addition is preferably carried out in a controlledmanner, e.g., adding dropwise at a reduced temperature such as, forexample, at about 0° C. The product can be isolated by conventionalmethods or it can be carried on without isolation as described below inconnection with step (7).

[0162] In step (7) of Reaction Scheme I a compound of Formula IX isreacted with an amine of formula R₁NH₂ where R₁ is as defined above toprovide a 4-nitrotetrazolo[1,5-a][1,8]naphthyridin-5-amine of Formula X.The reaction can be carried out by adding the amine to the reactionmixture resulting from step (6). The reaction can also be carried out byadding the amine to a solution of the compound of Formula IX and atertiary amine in a suitable solvent such as dichloromethane.

[0163] In step (8) of Reaction Scheme I a compound of Formula X isreduced to provide a tetrazolo[1,5-a][1,8]naphthyridin-4,5-diamine ofFormula XI. Preferably, the reduction is carried out using aconventional heterogeneous hydrogenation catalyst such as platinum oncarbon or palladium on carbon. The reaction can conveniently be carriedout on a Parr apparatus in a suitable solvent such as ethanol.

[0164] In step (9) of Reaction Scheme I a compound of Formula XI isreacted with a carboxylic acid or an equivalent thereof to provide a1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridine of Formula XII.Suitable equivalents to carboxylic acid include acid halides,orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid orequivalent is selected such that it will provide the desired R₂substituent in a compound of Formula XII. For example,diethoxymethylacetate will provide a compound where R₂ is hydrogen andvaleryl chloride will provide a compound where R₂ is butyl. The reactioncan be run in the absence of solvent, in a carboxylic acid such asacetic acid, or in an inert solvent in the presence of a carboxylicacid. The reaction is run with sufficient heating to drive off anyalcohol or water formed as a byproduct of the reaction.

[0165] In step (10) of Reaction Scheme I a compound of Formula XII isreacted with triphenylphosphine to provide aN-triphenylphosphinyl-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine ofFormula XIII. The reaction can be carried out by combining a compound ofFormula XII with triphenylphosphine in a suitable solvent such as1,2-dichlorobenzene and heating.

[0166] In step (11) of Reaction Scheme I a compound of Formula XIII ishydrolyzed to provide a 1H-imidazo[4,5-c][1,8]naphthyridin-4-amine ofFormula XIV which is a subgenus of Formula I. The hydrolysis can becarried out by conventional methods such as by heating in a loweralkanol in the presence of an acid. The product or a pharmaceuticallyacceptable salt thereof can be isolated using conventional methods.

[0167] In step (12) of Reaction Scheme I a compound of Formula XIV isreduced to provide a6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine of FormulaXV which is a subgenus of Formula II. The reduction is carried out bysuspending or dissolving a compound of Formula XIV in trifluoroaceticacid, adding a catalytic amount of platinum (IV)oxide, and thensubjecting the mixture to hydrogen pressure. The reaction can beconveniently carried out in a Parr apparatus. The product or apharmaceutically acceptable salt thereof can be isolated usingconventional methods.

[0168] Alternatively, as illustrated in step (13) of Reaction Scheme I,a 6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine ofFormula XV can be prepared by reduction of a compound of Formula XII.The reduction is carried out by suspending or dissolving a compound ofFormula XII in trifluoroacetic acid, adding a catalytic amount ofplatinum (IV)oxide, and then subjecting the mixture to hydrogenpressure. The reaction can be conveniently carried out in a Parrapparatus. As above, the product or a pharmaceutically acceptable saltthereof can be isolated using conventional methods.

[0169] Compounds of Formulas I and II wherein A is ═CR—N═CR—CR═or B is—C(R)₂—NR—C(R)₂—C(R)₂—; R, R₁ and R₂ are as defined above can beprepared according to Reaction Scheme II.

[0170] In step (1) of Reaction Scheme II a 3-aminoisonicotinic acid ofFormula XVI is reacted with acetic anhydride by heating to provide a2-methyl-4H-pyrido[3,4-d][1,3]oxazin-4-one of Formula XVII. The compoundof Formula XVII where R is hydrogen is known and its preparation hasbeen disclosed in Littell cited above.

[0171] In step (2) of Reaction Scheme II a compound of Formula XVII isreacted with sodium azide in a suitable solvent such as acetic acid toprovide a tetrazolyl isonicotinic acid of Formula XVIII. The reactionconveniently may be run at ambient conditions.

[0172] In step (3) of Reaction Scheme II an acid of Formula XVIII isesterified to provide a compound of Formula XIX. The esterification maybe carried out using conventional methods. For example, the acid may beesterified in acetone using potassium carbonate and ethyl iodide or byreacting with dimethylformamide diethyl acetal in a suitable solventsuch as dichloromethane.

[0173] In step (4) of Reaction Scheme II a compound of Formula XIX iscyclized to provide a tetrazolo[1,5-a][1,7]naphthyridin-5-ol of FormulaXX. The reaction maybe carried out by reacting the compound of FormulaXIX with an alkoxide in a suitable solvent, e.g., potassium ethoxide inN,N-dimethylformamide, at ambient conditions.

[0174] In step (5) of Reaction Scheme II a compound of Formula XX ischlorinated using a suitable chlorinating agent such as thionylchloride, oxalyl chloride, phosphorus pentachloride or preferablyphosphorus oxychloride to provide a5-chlorotetrazolo[1,5-a][1,7]naphthyridine of Formula XXI. The reactioncan be carried out in an inert solvent or if appropriate in neatchlorinating agent. Preferred reaction conditions involve reaction inneat phosphorus oxychloride with heating at about 90° C.

[0175] In step (6) of Reaction Scheme II a compound of Formula XXI isreacted with an amine of formula R₁NH₂ where R₁ is as defined above toprovide a tetrazolo[1,5-a][1,7]naphthyridin-5-amine of Formula XXII. Thereaction can be carried out by heating with an excess of the amine.

[0176] In step (7) of Reaction Scheme II a compound of Formula XXII isnitrated using a suitable nitrating agent such as nitric acid to providea 4-nitrotetrazolo[1,5-a][1,7]naphthyridin-5-amine of Formula XXIII.Preferably the reaction is carried out in acetic acid with mild heatingand an excess of nitric acid.

[0177] In step (8) of Reaction Scheme II a compound of Formula XXIII isreduced to provide a tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine ofFormula XXIV. Preferably the reduction is carried out using an excess ofsodium hydrogensulfide in a suitable solvent such as acetic acid.

[0178] In step (9) of Reaction Scheme II a compound of Formula XXIV isreacted with a carboxylic acid or an equivalent thereof to provide a1H-tetrazolo[1,5-a]imidazo[4,5-c][1,7]naphthyridine of Formula XXV.Suitable equivalents to carboxylic acid include acid halides,orthoesters, and 1,1-dialkoxyalkyl alkanoates. The carboxylic acid orequivalent is selected such that it will provide the desired R₂substituent in a compound of Formula XXV. For example,diethoxymethylacetate will provide a compound where R₂ is hydrogen andvaleryl chloride will provide a compound where R₂ is butyl. The reactioncan be run in the absence of solvent, in a carboxylic acid such asacetic acid, or in an inert solvent in the presence of a carboxylicacid. The reaction is run with sufficient heating to drive off anyalcohol or water formed as a byproduct of the reaction.

[0179] In step (10) of Reaction Scheme II a compound of Formula XXV isreacted with triphenylphosphine to provide aN-triphenylphosphinyl-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine ofFormula XXVI. The reaction can be carried out by combining a compound ofFormula XXV with triphenylphosphine in a suitable solvent such as1,2-dichlorobenzene and heating.

[0180] In step (11) of Reaction Scheme II a compound of Formula XXVI ishydrolyzed to provide a 1H-imidazo[4,5-c][1,7]naphthyridin-4-amine ofFormula XXVII which is a subgenus of Formula I. The hydrolysis can becarried out by conventional methods such as by heating in a loweralkanol in the presence of an acid. The product or a pharmaceuticallyacceptable salt thereof can be isolated using conventional methods.

[0181] In step (12) of Reaction Scheme II a compound of Formula XXVII isreduced to provide a6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine of FormulaXXVIII which is a subgenus of Formula II. The reduction is carried outby suspending or dissolving a compound of Formula XXVII intrifluoroacetic acid, adding a catalytic amount of platinum (IV)oxide,and then subjecting the mixture to hydrogen pressure. The reaction canbe conveniently carried out in a Parr apparatus. The product or apharmaceutically acceptable salt thereof can be isolated usingconventional methods.

[0182] Alternatively, as illustrated in step (13) of Reaction Scheme II,a 6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine ofFormula XXVII can be prepared by reduction of a compound of Formula XXV.The reduction is carried out by suspending or dissolving a compound ofFormula XXV in trifluoroacetic acid, adding a catalytic amount ofplatinum (IV)oxide, and then subjecting the mixture to hydrogenpressure. The reaction can be conveniently carried out in a Parrapparatus. The product or a pharmaceutically acceptable salt thereof canbe isolated using conventional methods.

[0183] Compounds of Formulas I and II wherein A is ═CR—CR═CR—N=or B is—C(R)₂—C(R)₂—C(R)₂—NR— and R, R₁ and R₂ are as defined above can beprepared according to Reaction Scheme III.

[0184] In step (1) of Reaction Scheme III a3-nitro[1,5]naphthyridin-4-ol of Formula XXIX is chlorinated using asuitable chlorinating agent such as phosphorus oxychloride to provide a4-chloro-3-nitro[1,5]naphthyridine of Formula XXX. The reaction can becarried out by reacting a compound of Formula XXIX with phosphorusoxychloride in a suitable solvent such as N,N-dimethylformamide withmild heating (˜55° C.). The compound may be isolated by conventionalmethods or it can be carried on without isolation as described below inconnection with step (2). The compound of Formula XXIX where R ishydrogen is known and its preparation has been disclosed in Hart,Journal of the Chemical Society pp. 212-214, (1956).

[0185] In step (2) of Reaction Scheme III a4-chloro-3-nitro[1,5]naphthyridine of Formula XXX is reacted with anamine of Formula R₁NH₂ where R₁ is as defined above to provide a3-nitro[1,5]naphthyridin-4-amine of Formula XXXI. The reaction can becarried out by adding water then excess amine to the reaction mixtureresulting from step (1) then heating on a steam bath. The reaction canalso be carried out by adding excess amine to a solution of a compoundof Formula XXX in a suitable solvent such as dichloromethane andoptionally heating. The compound of Formula XXXI where R₁ is hydrogen isknown and its preparation has been disclosed in Wozniak et al, J. R.Neth. Chem. Soc. 102 (12), pp. 511-13 (1983).

[0186] In step (3) of Reaction Scheme III a3-nitro[1,5]naphthyridin-4-amine of Formula XXXI is reduced to provide a[1,5]naphthyridine-3,4-diamine of Formula XXXII. Preferably, thereduction is carried out using a conventional heterogeneoushydrogenation catalyst such as platinum on carbon or palladium oncarbon. The reaction can conveniently be carried out on a Parr apparatusin a suitable solvent such as ethyl acetate.

[0187] In step (4) of Reaction Scheme III a compound of Formula XXXII isreacted with a carboxylic acid or an equivalent thereof to provide a1H-imidazo[4,5-c][1,5]naphthyridine of Formula XXXIII. Suitableequivalents to carboxylic acid include acid halides, orthoesters, and1,1-dialkoxyalkyl alkanoates. The carboxylic acid or equivalent isselected such that it will provide the desired R₂ substituent in acompound of Formula XXXIII. For example, diethoxymethylacetate willprovide a compound where R₂ is hydrogen and trimethylorthovalerate willprovide a compound where R₂ is butyl. The reaction can be run in theabsence of solvent, in a carboxylic acid such as acetic acid, or in aninert solvent in the presence of an acid. The reaction is run withsufficient heating to drive off any alcohol or water formed as abyproduct of the reaction.

[0188] Alternatively, step (4) may be carried out by (i) reacting acompound of Formula XXXII with an acylating agent; and then (ii)cyclizing the product. Part (i) involves reacting a compound of FormulaXXXII with an acyl halide of formula R₂C(O)X wherein R₂ is as definedabove and X is chloro or bromo. The reaction can be carried out byadding the acyl halide in a controlled fashion (e.g. dropwise) to asolution of a compound of Formula XXXII in a suitable solvent such asdichloromethane at a reduced temperature (e.g., 0° C.). The resultingamide intermediate can be isolated by removal of the solvent. Part (ii)involves cyclizing the product of part (i) by reacting it withmethanolic ammonia at an elevated temperature (e.g. 150° C.) andpressure.

[0189] In step (5) of Reaction Scheme III a compound of Formula XXXIIIis oxidized to provide a 1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide ofFormula XXXIV using a conventional oxidizing agent that is capable offorming N-oxides. Preferred reaction conditions involve reacting asolution of a compound of Formula XXXIII in chloroform with3-chloroperoxybenzoic acid at ambient conditions.

[0190] In step (6) of Reaction Scheme III a compound of Formula XXXIV isaminated to provide a 1H-imidazo[4,5-c][1,5]naphthyridin-4-amine ofFormula XXXV which is a subgenus of Formula I. Step (6) involves (i)reacting a compound of formula XXXIV with an acylating agent; and then(ii) reacting the product with an aminating agent. Part (i) of step (6)involves reacting an N-oxide with an acylating agent. Suitable acylatingagents include alkyl- or arylsulfonyl chlorides (e.g., benzenesulfonylchloride, methanesulfonyl choride, p-toluenesulfonyl chloride).Arylsulfonyl chlorides are preferred. p-Toluenesulfonyl chloride is mostpreferred. Part (ii) of step (6) involves reacting the product of part(i) with an excess of an aminating agent. Suitable aminating agentsinclude ammonia (e.g., in the form of ammonium hydroxide) and ammoniumsalts (e.g., ammonium carbonate, ammonium bicarbonate, ammoniumphosphate). Ammonium hydroxide is preferred. The reaction is preferablycarried out by dissolving the N-oxide of Formula XXXIV in an inertsolvent such as dichloromethane, adding the aminating agent to thesolution, and then adding the acylating agent. Preferred conditionsinvolve cooling to about 0° C. to about 5° C. during the addition of theacylating agent. The product or a pharmaceutically acceptable saltthereof can be isolated using conventional methods.

[0191] Alternatively step (6) may be carried out by (i) reacting acompound of Formula XXXIV with an isocyanate; and then (ii) hydrolyzingthe product. Part (i) involves reacting the N-oxide with an isocyanatewherein the isocyanato group is bonded to a carbonyl group. Preferredisocyanates include trichloroacetyl isocyanate and aroyl isocyanatessuch as benzoyl isocyanate. The reaction of the isocyanate with theN-oxide is carried out under substantially anhydrous conditions byadding the isocyanate to a solution of the N-oxide in an inert solventsuch as dichloromethane. The resulting product can be isolated byremoval of the solvent. Part (ii) involves hydrolysis of the productfrom part (i). The reaction can be carried out by conventional methodssuch as heating in the presence of water or a lower alkanol optionallyin the presence of a catalyst such as an alkali metal hydroxide or loweralkoxide.

[0192] In step (7) of Reaction Scheme III a compound of Formula XXXV isreduced to provide a6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine of FormulaXXXVI which is a subgenus of Formula II. The reduction is carried out bysuspending or dissolving a compound of Formula XXXV in trifluoroaceticacid, adding a catalytic amount of platinum (IV) oxide, and thensubjecting the mixture to hydrogen pressure. The reaction can beconveniently carried out in a Parr apparatus. The product or apharmaceutically acceptable salt thereof can be isolated usingconventional methods.

[0193] Certain functional groups recited in connection with R₁ and R₂may be incompatible with some of the reagents of Reaction Schemes I, IIand III. Compounds containing such functional groups can be prepared bythose skilled in the art using well known methods of functional groupprotection and manipulation. For example, amine groups may be protectedwhen necessary by derivatizing with di-tert-butyl dicarbonate.

[0194] Some compounds of Formula I or Formula II containing certainfunctional groups may be readily prepared from other compounds ofFormula I or Formula II. For example, compounds wherein the R₁substituent contains an amide group may conveniently be prepared byreacting an acid chloride with a compound of Formula I or Formula IIwherein the R₁ substituent contains a primary amine. Likewise, compoundswherein the R₁ substituent contains a urea group may be prepared byreacting an isocyanate with a compound of Formula I or Formula IIwherein the R₁ substituent contains a primary amine. Further, compoundswherein the R₁ substituent contains a carbamate group may be prepared byreacting a chloroformate with a compound of Formula I or Formula IIwherein the R₁ substituent contains a primary amine.

[0195] Certain of the intermediate compounds useful in the preparationof compounds of Formula I and Formula II have not been previouslydescribed. Therefore, the invention also provides intermediate compoundsuseful in the preparation of compounds of Formula I and Formula II. Thestructural formulas of these novel intermediates are set forth below.These compounds have the following structural formulas:

Intermediate Compound 1

[0196]

[0197] wherein R₁, R₂ and A are as defined above for compounds ofFormula I and Formula II.

Intermediate Compound 2

[0198]

[0199] wherein R, R₁, and R₂ are as defined above for compounds ofFormula I and Formula II.

Intermediate Compound 3

[0200]

[0201] wherein R, R₁ and R₂ are as defined above for compounds ofFormula I and Formula II.

Intermediate Compound 4

[0202]

[0203] wherein R₇ is OH, halogen or NHR₁ (and A and R₁ are as definedabove for compounds of Formula I) and R₈ is H, NO₂ or NH₂.

Intermediate Compound 5

[0204]

[0205] wherein A is as defined above for compounds of Formula I and R₉is H or C₁₋₁₀ alkyl.

Intermediate Compound 6

[0206]

[0207] wherein R and R₁ are as defined above for compounds of Formula Iand Formula II with the proviso that R₁ is other than hydrogen, and R₁₀is NO₂ or NH₂.

[0208] Pharmaceutical Compositions and Biological Activity

[0209] Pharmaceutical compositions of the invention contain atherapeutically effective amount of a compound of Formula I or FormulaII as defined above in combination with a pharmaceutically acceptablecarrier. As used herein, the term “a therapeutically effective amount”means an amount of the compound sufficient to induce a therapeuticeffect, such as cytokine induction or antiviral activity. Although theexact amount of active compound used in a pharmaceutical composition ofthe invention will vary according to factors known to those of skill inthe art, such as the physical and chemical nature of the compound aswell as the nature of the carrier and the intended dosing regimen, it isanticipated that the compositions of the invention will containsufficient active ingredient to provide a dose of about 100 ng/kg toabout 50 mg/kg, preferably about 10 μg/kg to about 5 mg/kg of thecompound to the subject. Any of the conventional dosage forms may beused, such as tablets, lozenges, parenteral formulations, syrups,creams, ointments, aerosol formulations, transdermal patches,transmucosal patches and so on.

[0210] The compounds of the invention have been shown to induce theproduction of certain cytokines in experiments performed according tothe Test Method set forth below. This ability indicates that thecompounds are useful as immune response modifiers that can modulate theimmune response in a number of different ways, rendering them useful inthe treatment of a variety of disorders.

[0211] Cytokines that are induced by the administration of compoundsaccording to the invention generally include interferon (IFN) and tumornecrosis factor (TNF) as well as certain interleukins (IL). Inparticular, the compounds induce IFN-α, TNF-α, IL-1, 6, 10 and 12, and avariety of other cytokines. Among other effects, cytokines inhibit virusproduction and tumor cell growth, making the compounds useful in thetreatment of tumors and viral diseases.

[0212] In addition to the ability to induce the production of cytokines,the compounds affect other aspects of the innate immune response. Forexample, natural killer cell activity may be stimulated, an effect thatmay be due to cytokine induction. The compounds may also activatemacrophages, which in turn stimulates secretion of nitric oxide and theproduction of additional cytokines. Further, the compounds may causeproliferation and differentiation of B-lymphocytes.

[0213] Compounds of the invention also have an effect on the acquiredimmune response. For example, although there is not believed to be anydirect effect on T cells or direct induction of T cell cytokines, theproduction of the T helper type 1 (Th1) cytokine IFN-γ is inducedindirectly and the production of the Th2 cytokine IL-5 is inhibited uponadministration of the compounds. This activity means that the compoundsare useful in the treatment of diseases where upregulation of the Th1response and/or downregulation of the Th2 response is desired. In viewof the ability of compounds of Formula I and Formula II to inhibitT-helper-type 2 immune response, the compounds are expected to be usefulin the treatment of atopy, e.g., atopic dermatitis, asthma, allergy,allergic rhinitis; as a vaccine adjuvant for cell mediated immunity; andpossibly as a treatment for recurrent fungal diseases and chlamydia.

[0214] The immune response modifying effects of the compounds make themuseful in the treatment of a wide variety of conditions. Because oftheir ability to induce cytokines such as IFN-α and TNF-α, the compoundsare particularly useful in the treatment of viral diseases and tumors.This immunomodulating activity suggests that compounds of the inventionare useful in treating diseases such as, but not limited to viraldiseases e.g. genital warts, common warts, plantar warts, Hepatitis B,Hepatitis C, Herpes Simplex Type I and Type II, molluscum contagiosm,HIV, CMV, VZV, cervical intraepithelial neoplasia, human papillomavirusand associated neoplasias; fungal diseases, e.g. candida, aspergillus,cryptococcal meningitis; neoplastic diseases, e.g., basal cellcarcinoma, hairy cell leukemia, Kaposi's sarcoma, renal cell carcinoma,squamous cell carcinoma, myelogenous leukemia, multiple myeloma,melanoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, and othercancers; parasitic diseases, e.g. pneumocystis camii, cryptosporidiosis,histoplasmosis, toxoplasmosis, trypanosome infection, leishmaniasis;bacterial infections, e.g., tuberculosis, mycobacterium avium.Additional diseases or conditions that can be treated using thecompounds of the invention include eczema, eosinophilia, essentialthrombocythaemia, leprosy, multiple sclerosis, Ommen's syndrome,rheumatoid arthritis, systemic lupus erythematosis, discoid lupus,Bowen's disease, and Bowenoid papulosis.

[0215] Accordingly, the invention provides a method of inducing cytokinebiosynthesis in an animal comprising administering an effective amountof a compound of Formula I or Formula II to the animal. An amount of acompound effective to induce cytokine biosynthesis is an amountsufficient to cause one or more cell types, such as monocytes,macrophages, dendritic cells and B-cells to produce an amount of one ormore cytokines such as, for example, INF-

, TNF-

, IL-1, 6, 10 and 12 that is increased over the background level of suchcytokines. The precise amount will vary according to factors known inthe art but is expected to be a dose of about 100 ng/kg to about 50mg/kg, preferably about 10 μg/kg to about 5 mg/kg. The invention furtherprovides a method of treating a viral infection in an animal comprisingadministering an effective amount of a compound of Formula I or FormulaII to the animal. An amount effective to treat or inhibit a viralinfection is an amount that will cause a reduction in one or more of themanifestations of viral infection, such as viral lesions, viral load,rate of virus production, and mortality as compared to untreated controlanimals. The precise amount will vary according to factors known in theart but is expected to be a dose of 100 ng/kg to about 50 mg/kg,preferably about 10 μg/kg to about 5 mg/kg.

[0216] The invention is further described by the following examples,which are provided for illustration only and are not intended to belimiting in any way.

EXAMPLE 1 Compound of Formula V 2-(5-Methyl-1H-tetrazol-1-yl)nicotinicAcid

[0217] Part A:

[0218] 2-Aminonicotinic acid (5 g, 36 mmole) was suspended in aceticanhydride (25 mL) then heated at reflux for 2 hours. The reactionmixture was concentrated under vacuum. The resulting residue wasslurried with ethyl acetate and hexane then filtered to provide 5 g of2-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-one.

[0219] Part B:

[0220] The material from Part A was covered with acetic acid (75 mL),sodium azide (2 g) was added and the reaction mixture was stirred atambient temperature over the weekend. The resulting precipitate wasisolated by filtration then dried to provide 5.6 g of2-(5-methyl-1H-tetrazol-1-yl)nicotinic acid as a white solid, m.p.178-180° C. (gas evolution). Analysis: Calculated for C₈H₇N₅O₂: % C,46.83; % H, 3.44; % N, 34.13; Found: % C, 46.38; % H, 3.36; % N, 34.01.

EXAMPLE 2 Compound of Formula VI Ethyl2-(5-Methyl-1H-tetrazol-1-yl)nicotinate

[0221] 2-(5-Methyl-1H-tetrazol-1-yl)nicotinic acid (5.6 g, 27 mmole) wassuspended in acetone (250 mL), potassium carbonate (5 g) and ethyliodide (5 mL) were added and the reaction mixture was heated at refluxfor 2 hours. The acetone was removed under vacuum. The residue waspartitioned between water and dichloromethane. The dichloromethane layerwas separated, dried, then concentrated under vacuum to provide 6.3 g ofethyl 2-(5-methyl-1H-tetrazol-1-yl)nicotinate.

EXAMPLE 3 Compound of Formula VII Tetrazolo[1,5-a][1,8]naphthyridin-5-ol

[0222] Ethyl 2-(5-methyl-1H-tetrazol-1-yl)nicotinate (6.3 g, 27 mmole)was covered with N,N-dimethylformamide (50 mL), potassium ethoxide (4.5g, 54 mmole) was added and the reaction mixture was stirred at ambienttemperature for 2 hours. The reaction mixture was poured into ice watercontaining about 17 mL of acetic acid. The resulting precipitate wasisolated by filtration, washed with water then dried to provide 4.5 g oftetrazolo[1,5-a][1,8]naphthyridin-5-ol as an off white solid, m.p. 236°(decomposition). Analysis: Calculated for C₈H₅N₅O: % C, 51.34; % H,2.69; % N, 37.42; Found: % C, 51.23; % H, 2.77; % N, 37.25.

EXAMPLE 4 5-Chlorotetrazolo[1,5-a][1,8]naphthyridine

[0223] Tetrazolo[1,5-a][1,8]naphthyridin-5-ol (0.5 g, 2.67 mmole) wassuspended in phosphorous oxychloride (10 mL) and heated at reflux for 4hours. The reaction mixture was concentrated under vacuum and theresidue was poured into water. Dichloromethane was added and the aqueouslayer was made basic with sodium bicarbonate. The dichloromethane layerwas separated, dried over magnesium sulfate, filtered and thenconcentrated under vacuum. The resulting solid was recrystallized fromtoluene to provide 0.3 g of 5-chlorotetrazolo[1,5-a][1,8]naphthyridineas a solid, m.p. 229-230° C. (decomposition). Analysis: Calculated forC₈H₄ClN₅: % C, 46.73; % H, 1.96; % N, 34.06; Found: % C, 46.87; % H,1.54; % N, 33.93.

EXAMPLE 5 Compound of Formula VIII4-Nitrotetrazolo[1,5-a][1,8]naphthryidin-5-ol

[0224] Nitric acid (1.33 mL of 16M) was added to a suspension oftetrazolo[1,5-a][1,8]naphthyridin-5-ol (4 g, 21 mmole) in acetic acid(50 mL). The reaction mixture was heated on a steam bath for 5 minutesthen cooled to ambient temperature. Sodium acetate (0.3 eq) in a smallamount of water was added to the reaction mixture. The resulting solidwas isolated by filtration and dried to provide 5 g of4-nitrotetrazolo[1,5-a][1,8]naphthryidin-5-ol as a solid, m.p. 278° C.(decomposition). Analysis: Calculated for C₈H₄N₆O₃+1.1H₂O: % C, 38.12; %H, 2.48; % N, 33.35; Found: % C, 37.99; % H, 2.41; % N, 32.82.

EXAMPLE 6 Compound of Formula XN⁵-(2-Methylpropyl)-4-nitrotetrazolo[1,5-a][1,8]naphthyridin-5-amine

[0225] 4-Nitrotetrazolo[1,5-a][1,8]naphthryidin-5-ol (3 g, 13 mmole) wassuspended in dichloromethane (3.8 mL), triethylamine (1.8 mL) was added,and the reaction mixture was cooled in an ice bath.Trifluoromethanesulfonic anhydride (2.2 mL) was added dropwise.Isobutylamine (3.8 mL) was added in a single aliquot and the reactionmixture exothermed. The reaction mixture was partitioned betweendichloromethane and aqueous sodium bicarbonate. The dichloromethanelayer was separated, dried over magnesium sulfate then filtered througha layer of silica gel. The silica gel was eluted first withdichloromethane then with 5% methanol in dichloromethane. The eluant wasevaporated to provideN⁵-(2-methylpropyl)-4-nitrotetrazolo[1,5-a][1,8]naphthyridine-5-amine asa yellow solid, m.p. 171° C. (decomposition). Analysis: Calculated forC₁₂H₁₃N₇O₂: % C, 50.17; % H, 4.56; % N, 34.13; Found: % C, 49.84; % H,4.51; % N, 33.88.

EXAMPLE 7 Compound of Formula XIN⁵-(2-Methylpropyl)tetrazolo[1,5-a][1,8]naphthyridin-4,5-diamine

[0226] A catalytic amount of 5% platinum on carbon was added to asuspension ofN⁵-(2-methylpropyl)-4-nitrotetrazolo[1,5-a][1,8]naphthyridine-5-amine(2.45 g, 8.5 mmoles) in ethanol (120 mL). The reaction mixture wasreduced on a Parr apparatus at 50 psi (3.5 Kg/cm²) hydrogen for 2 hours.The reaction mixture was filtered to remove the catalyst. The filtratewas concentrated under vacuum to provideN⁵-(2-methylpropyl)tetrazolo[1,5-a][1,8]naphthyridin-4,5-diamine as anoil.

EXAMPLE 8 Compound of Formula XII1-(2-Methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridine

[0227] TheN⁵-(2-methylpropyl)tetrazolo[1,5-a][1,8]naphthyridin-4,5-diamine fromExample 7 was combined with diethoxymethylacetate (2 mL) and heated on asteam bath for 3 hours. The reaction mixture was allowed to stand atambient temperature overnight and then it was diluted withdichloromethane and methanol. The resulting solution was heated toremove the dichloromethane and reduce the volume of methanol to 50 mLand then cooled. The resulting precipitate was isolated by filtration toprovide 1.2 g of1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridineas a solid, m.p. 248-250° C. (decomposition). Analysis: Calculated forC₁₃H₁₃N₇: % C, 58.42; % H, 4.90; % N, 36.68; Found: % C, 58.04; % H,4.79; % N, 36.23.

EXAMPLE 9 Compound of Formula I1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine hydrate

[0228]

[0229] Part A:

[0230] Triphenylphosphine (1.0 g, 3.7 mmole) was added to a solution of1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridine(0.5 g, 1.87 mmole) in 1,2-dichlorobenzene (15 mL). The reaction mixturewas heated at reflux for 2 hours then concentrated under vacuum toremove the majority of the 1,2-dichlorobenzene. The residue was slurriedwith hexanes for 30 minutes. The resulting solid1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,8]naphthyridin-4-aminewas isolated by filtration and dried.

[0231] Part B:

[0232] The1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,8]naphthyridin-4-aminefrom Part A was dissolved in methanol (15 mL). Hydrochloric acid (10 mLof 0.6N) was added and the reaction mixture was heated at reflux for 1hour. The reaction mixture was concentrated under vacuum. The residuewas diluted with water then made basic with sodium bicarbonate. Theresulting solid was isolated by filtration, slurried with ether and thenisolated by filtration. The solid was suspended in toluene (25 mL). Thesuspension was heated to reflux then diluted with methanol (10 mL) todissolve the solid. The solution was refluxed to remove the methanolthen cooled to ambient temperature. The resulting precipitate wasisolated by filtration then coated onto silica gel. The silica gel waseluted with 10-20% methanol in ethyl acetate. The eluant wasconcentrated to dryness. The resulting material was recrystallized frommethanol and water to provide 0.35 g1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine hydrate asa solid, m.p. 325-330° C. (decomposition). Analysis: Calculated forC₁₃H₁₅N₅+¼H₂O: % C, 63.52; % H, 6.35; % N, 28.49; Found: % C, 64.02; %H, 5.87; % N, 28.23.

EXAMPLE 10 Compound of Formula II6,7,8,9-Tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine

[0233]

[0234] Platinum oxide catalyst was added to a solution of1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridinein trifluoroacetic acid (30 mL). The reaction mixture was reduced on aParr apparatus at 50 psi (3.5 Kg/cm²) hydrogen pressure for 5 hours. Thereaction mixture was filtered to remove the catalyst. The filtrate wasconcentrated under vacuum. The residue was combined with water andsodium bicarbonate. The resulting precipitate was isolated byfiltration. The solid was dissolved in 1N hydrochloric acid and charcoalfiltered. The filtrate was treated with 10% sodium hydroxide. Theresulting precipitate was isolated by filtration then recrystallizedfrom ethyl acetate/methanol. The recrystallized material was dissolvedin dichloromethane/methanol and placed on a silica gel column. Thecolumn was eluted with 10% methanol in ethyl acetate. The eluant wasconcentrated under vacuum and the residue was recrystallized frommethanol/water to provide 0.9 g of6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amineas a solid, m.p. 231-233° C. Analysis: Calculated for C₁₃H₁₉N₅: % C,63.65; % H, 7.81; % N, 28.55; Found: % C, 62.99; % H, 7.74; % N, 28.33.

EXAMPLE 11 Compound of Formula XII2-Butyl-1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridine

[0235] A catalytic amount of 5% platinum on carbon was added to asuspension ofN⁵-(2-methylpropyl)-4-nitrotetrazolo[1,5-a][1,8]naphthyridine-5-amine (5g, 17.4 mmoles) in ethanol (300 mL). The reaction mixture was reduced ona Parr apparatus at 50 psi (3.5 Kg/cm²) hydrogen for 2 hours. Thereaction mixture was filtered to remove the catalyst. The filtrate wasconcentrated under vacuum to provideN⁵-(2-methylpropyl)tetrazolo[1,5-a][1,8]naphthyridin-4,5-diamine as anoil.

[0236] The oil was covered with acetic acid (300 mL), valeryl chloride(2.1 mL, 17.4 mmole) was added and the resulting mixture was heated atreflux overnight. The reaction mixture was concentrated under vacuum.The resulting residue was taken up in dichloromethane, washed withsodium bicarbonate, dried over magnesium sulfate then concentrated undervacuum. The residue was purified using flash chromatography (silica gel;eluting with 2-3% methanol in dichloromethane). The isolated product waspurified further using preparatory high performance liquidchromatography eluting with 2% methanol in dichloromethane to provide2-butyl-1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridineas a solid, m.p. 182-184° C. Analysis: Calculated for C₁₇H₂₁N₇: % C,63.14; % H, 6.55; % N, 30.32; Found: % C, 63.45; % H, 6.60; % N, 30.40.

EXAMPLE 12 Compound of Formula I2-Butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine

[0237]

[0238] Triphenylphosphine (0.9 g, 3.7 mmole) was added to a solution of2-butyl-1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,8]naphthyridine(0.6 g, 1.8 mmole) in 1,2-dichlorobenzene (15 mL). The resulting mixturewas heated at reflux for 2 hours then concentrated under vacuum toremove most of the 1,2-dichlorobenzene. The residue was slurred withhexanes then taken up in dichloromethane and filtered through a layer ofsilica gel. The silica gel was eluted initially with dichloromethane toremove the 1,2-dichlorobenzene and then with 10% methanol indichloromethane to recover2-butyl-1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine.

[0239] The2-butyl-1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,8]naphthyridin-4-aminewas taken up in methanol (15 mL), combined with hydrochloric acid (10 mLof 0.6N), and then heated at reflux for 1 hour. The methanol was removedunder vacuum. The residue was combined with water and 10% hydrochloricacid then filtered. The filtrate was neutralized with 10% sodiumhydroxide. The resulting precipitate was isolated by filtration anddried. The resulting solid was refluxed in toluene. The volume oftoluene was reduced and the product was allowed to crystallize out underan argon atmosphere to provide 0.25 g of2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-aminehemihydrate, m.p. 237-240° C. Analysis: Calculated for C₁₇H₂₃N₅+½H₂O: %C, 68.66; % H, 7.79; % N, 23.55; Found: % C, 66.80; % H, 7.62; % N,23.46.

EXAMPLE 13 Compound of Formula II2-Butyl-6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine

[0240]

[0241] A catalytic amount of platinum oxide Was added to a solution of2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-amine(2.0 g, 6.2 mmole) in trifluoroacetic acid (30 mL). The reaction mixturewas reduced on a Parr apparatus under 50 psi (3.5 Kg/cm²) hydrogenpressure. The reaction mixture was filtered to remove the catalyst. Thefiltrate was concentrated under vacuum. The residue was combined withwater, sodium bicarbonate and 10% sodium hydroxide. An oil was recoveredand purified using reverse phase high performance liquid chromatographyeluting with 30:70 buffer (7.68 g potassium phosphate, monobasic; 1.69 gof sodium hydroxide, 1 L of water):methanol to provide2-butyl-6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,8]naphthyridin-4-aminehemihydrate as a solid, m.p. 81-84° C. Calculated for C₁₇H₂₇N₅+½H₂O: %C, 65.77; % H, 9.09; % N, 22.56; Found: % C, 65.57; % H, 9.15; % N,22.53.

EXAMPLE 14 Compound of Formula XVIII3-(5-Methyl-1H-tetrazol-1-yl)pyridine-4-carboxylic acid

[0242] 3-Aminopyridine-4-carboxylic acid (50.0 g, 0.36 mol) wassuspended in acetic anhydride (250 mL) then heated at reflux for 2hours. The reaction mixture was concentrated under vacuum. The solidresidue was slurried with heptane then concentrated under vacuum. Theresulting solid was covered with acetic acid (300 mL), then sodium azide(23.5 g, 0.36 mol) was added. The reaction exothermed to 50° C. Thereaction mixture was allowed to stir at ambient temperature overnight.The precipitate was isolated by filtration then slurried with methanoland filtered. The solid was dissolved in 10% sodium hydroxide. Thesolution was heated on a steam bath for 30 minutes, allowed to cool toambient temperature then neutralized with 6N hydrochloric acid. Theresulting precipitate was isolated by filtration, washed with water anddried to provide 64.5 g of3-(5-methyl-1H-tetrazol-1-yl)pyridine-4-carboxylic acid as an off whitesolid, m.p. 214-215° C. (decomposition).

EXAMPLE 15 Compound of Formula XIX Ethyl3-(5-Methyl-1H-tetrazol-1-yl)pyridine-4-carboxylate

[0243] Dimethylformamide diethyl acetal (46 mL) was added to asuspension of 3-(5-methyl-1H-tetrazol-1-yl)pyridine-4-carboxylic acid(36 g) in dichloromethane (800 mL). The reaction mixture was stirred atambient temperature overnight then washed six times with water (500 mL),dried over magnesium sulfated, and concentrated under vacuum. Theresidue was recrystallized from ethyl acetate/hexanes to provide 40 g ofethyl 3-(5-methyl-1H-tetrazol-1-yl)pyridine-4-carboxylate as a solid.

EXAMPLE 16 Compound of Formula XX Tetrazolo[1,5-a][1,7]naphthyridin-5-olhydrate

[0244] Potassium ethoxide (20.2 g) was added to a mixture of ethyl3-(5-methyl-1H-tetrazol-1-yl)pyridine-4-carboxylate (28 g) anddimethylformamide (280 mL). The reaction mixture was allowed to stir atambient temperature overnight then poured into cold dilute acetic acid.The resulting precipitate was collected, washed with water and dried toprovide 22.4 g of tetrazolo[1,5-a][1,7]naphthyridin-5-ol hydrate as asolid, m.p. 247-248° C. (decomposition). Analysis: Calculated forC₈H₅N₅O: % C, 46.83; % H, 3.44; % N, 34.13; Found: % C, 46.48; % H,3.42; % N, 34.03.

EXAMPLE 17 Compound of Formula XXI5-Chlorotetrazolo[1,5-a][1,7]naphthyridine

[0245] A suspension of tetrazolo[1,5-a][1,7]naphthyridin-5-ol (3.5 g) inphosphorous oxychloride (15 mL) was heated at 90° C. for 2 hours. Thereaction mixture was concentrated under vacuum. The residue was pouredinto ice water, dichloromethane was added followed by the addition of10% sodium hydroxide to neutral pH. The product was partitioned intodichloromethane. The dichloromethane layer was separated, dried overmagnesium sulfate then concentrated under vacuum to provide 3.8 g of5-chlorotetrazolo[1,5-a][1,7]naphthyridine as a solid, m.p. 176-177° C.Analysis: Calculated for C₈H₄ClN₅: % C, 46.73; % H, 1.96; % N, 34.06;Found: % C, 46.80; % H, 2.16; % N, 34.45.

EXAMPLE 18 Compound of Formula XXIIN⁵-(2-Methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-5-amine

[0246] A suspension of 5-chlorotetrazolo[1,5-a][1,7]naphthyridine (20 g)in isobutylamine (100 mL) was heated at reflux for several hours. Thereaction mixture was concentrated under vacuum. The residue was taken upin dichloromethane, washed with water, dried over magnesium sulfate thenconcentrated under vacuum. The residue was recrystallized from tolueneto give a material that was a mixture by thin layer chromatography. Thematerial was purified by flash chromatography, silica gel eluting withdichloromethane, 5-20% ethyl acetate in dichloromethane, and 10%methanol in dichloromethane. The fractions with the slower movingmaterial were concentrated to provideN⁵-(2-methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-5-amine as a solid,m.p. 220-221° C. Analysis: Calculated for C₁₂H₁₄N₆: % C, 59.49; % H,5.82; % N, 34.69; Found: % C, 59.35; % H, 5.89; % N, 34.88.

EXAMPLE 19 Compound of Formula XXIIIN⁵-(2-Methylpropyl)₄-nitrotetrazolo[1,5-a][1,7]naphthyridin-5-amine

[0247] Nitric acid (2 equivalents of 16M) was added to a solution ofN⁵-(2-methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-5-amine (2.0 g,8.26 mmol) in acetic acid. The reaction mixture was heated on a steambath for about an hour then concentrated under vacuum. The residue waspoured into ice water and the resulting mixture was neutralized withsodium bicarbonate. The resulting precipitate was extracted withdichloromethane. The dichloromethane extracts were combined, washed withwater, and dried over magnesium sulfate. Thin layer chromatographyindicated a mixture so the material was filtered through a layer ofsilica gel eluting with 5% ethyl acetate in dichloromethane. Thereaction was rerun on 4 g of starting material but using only oneequivalent of nitric acid. The resulting material was also a mixture.The material from both reactions was combined then purified by flashchromatography eluting with mixtures of hexanes/ethyl acetate. Thefractions containing the slower moving material were combined to provideabout 0.3 g ofN⁵-(2-methylpropyl)-4-nitrotetrazolo[1,5-a][1,7]naphthyridin-5-amine asa yellow solid, m.p. 173-174° C. Analysis: Calculated for C₁₂H₁₃N₇O₂: %C, 50.17; % H, 4.56; % N, 34.13; Found: % C, 49.85; % H, 4.53; % N,34.26.

EXAMPLE 20 Compound of Formula XXIVN⁵-(2-Methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine

[0248]N⁵-(2-Methylpropyl)-4-nitrotetrazolo[1,5-a][1,7]naphthyridin-5-amine(1.5 g, 5.22 mmol) was suspended in acetic acid (75 mL). An excess ofsodium hydrogen sulfide was dissolved in a minimum of water and added tothe suspension. The reaction mixture turned red and all of the materialwent into solution. The reaction mixture was extracted twice withdichloromethane (150 mL). The extracts were combined, washed with water,dried over magnesium sulfate, filtered and concentrated under vacuum toprovide 1.22 g ofN⁵-(2-methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine as alight yellow solid, m.p. 203-204.5° C. Analysis: Calculated for:C₁₂H₁₅N₇: % C, 56.02; % H, 5.88; % N, 38.11; Found: % C, 55.68; % H,5.81; % N, 37.74.

EXAMPLE 21 Compound of Formula XXV1-(2-Methylpropyl)-!H-tetrazolo[1,5-a]imidazo[4,5-c][1,7]naphthyridine

[0249] N⁵-(2-Methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine(1.1 g, 4.3 mmol) was combined with diethoxymethylacetate (2 mL) andheated on a steam bath overnight. The reaction mixture was partitionedbetween dichloromethane and ammonium hydroxide. The dichloromethanelayer was separated, washed with water, dried over magnesium sulfate andconcentrated under vacuum. The residue was recrystallized from ethylacetate/hexane to provide 0.85 g of1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,7]naphthyridineas a solid, m.p. 181-182.5° C. Analysis: Calculated for C₁₃H₁₃N₇: % C,58.42; % H, 4.90; % N, 36.68; Found: % C, 58.87; % H, 5.04; % N, 36.13.

EXAMPLE 22 Compound of Formula I1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine

[0250]

[0251] Part A:

[0252] Triphenylphosphine (0.49 g, 1.8 mmol) was added to a suspensionof1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,7]naphthyridine(0.24 g, 0.9 mmol) in dichlorobenzene (15 mL). The reaction mixture washeated at reflux overnight then concentrated under vacuum. The residuewas slurried with hexane and the resulting solid1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,7]naphthyridin-4-aminewas isolated by filtration.

[0253] Part B:

[0254] The1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,7]naphthyridin-4-aminefrom Part A was dissolved in methanol (30 mL). Hydrochloric acid (3 mLof 3N) was added to the solution and the reaction mixture was heated atreflux overnight before being concentrated under vacuum to remove themethanol. The aqueous residue was neutralized with sodium bicarbonatethen extracted with dichloromethane. The extract was dried overmagnesium sulfate then concentrated under vacuum. The residue waspurified by flash chromatography (silica gel eluting with 5-10% methanolin dichloromethane) to provide 0.15 g of1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine as asolid, m.p. 306-307° C. Analysis: Calculated for C₁₃H is N₅: % C, 64.71;% H, 6.27; % N, 29.02; Found: % C, 65.10; % H, 6.28; % N, 28.70.

EXAMPLE 23 Compound of Formula II6,7,8,9-Tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine

[0255]

[0256] A catalytic amount of platinum oxide was added to a solution of1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine (0.4 g,1.66 mol)) in trifluoroacetic acid. The reaction mixture was reduced ona Parr apparatus at 50 psi (3.5 Kg/cm²) hydrogen pressure overnight. Thereaction mixture was filtered and washed with methanol to remove thecatalyst. The filtrate was concentrated under vacuum. The residue wascombined with dichloromethane and aqueous sodium bicarbonate was addeduntil the mixture was basic. The dichloromethane layer was separated.The aqueous layer was extracted five times with dichloromethane (100mL). The dichloromethane extracts were combined, dried over magnesiumsulfate and concentrated under vacuum. The resulting residue wasrecrystallized from toluene to provide 0.34 g of6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amineas a solid, m.p. 220-223° C. Analysis: Calculated for C₁₃H₁₉N₅+¼H₂O: %C, 62.50% H, 7.87; % N, 28.03; Found: % C, 62.50; % H, 7.72; % N, 27.46.

EXAMPLE 24 Compound of Formula XXV2-Methyl-1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,7]naphthyridine

[0257] Acetic anhydride (2-3 mL) was added to a solution ofN-(2-methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine (0.8 g,3.1 mmole) in acetic acid. The reaction mixture was heated on a steambath for several hours then concentrated under vacuum. The residue waspartitioned between dichloromethane and water. The aqueous layer wasmade basic with 10% sodium hydroxide then the dichloromethane layer wasseparated, dried over magnesium sulfate and concentrated under vacuum.The residue was purified by flash chromatography (silica gel elutingwith 2-5% methanol in dichloromethane) to provide 0.25 g of2-methyl-1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,7]naphthyridineas a solid, m.p. 157-158° C. Analysis: Calculated for C₁₄H₁₅N₇: % C,59.77; % H, 5.37; % N, 34.85; Found: % C, 59.64; % H, 5.48; % N, 34.98.

EXAMPLE 25 Compound of Formula I2-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine

[0258]

[0259] Part A:

[0260] Triphenylphosphine (2.5 g, 9.6 mmol) was added to a suspension of2-methyl-1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,7]naphthyridine(1 g, 4 mmol) in dichlorobenzene. The reaction mixture was heated atreflux overnight then concentrated under vacuum. The residue wasslurried with hexane and the

[0261] resulting solid2-methyl-1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,7]naphthyridin-4-aminewas isolated by filtration.

[0262] Part B:

[0263] The2-methyl-1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,7]naphthyridin-4-aminefrom Part A was dissolved in methanol (100 mL). Hydrochloric acid (10 mLof 3N) was added to the solution and the reaction mixture was heated atreflux overnight before being concentrated under vacuum to remove themethanol. The residue was purified by flash chromatography (silica geleluting with dichloromethane and gradually increasing the polarity to 5%methanol in dichloromethane) to provide2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amineas a solid, m.p. 322-324° C. Analysis: Calculated for C₁₄H₁₇N₅: % C,65.86; % H, 6.71; % N, 27.43; Found: % C, 65.81; % H, 6.64; % N, 27.41.

EXAMPLE 26 Compound of Formula II6,7,8,9-Tetrahydro-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine

[0264]

[0265] A catalytic amount of platinum oxide was added to a solution of2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine(0.1 g, 0.4 mol) in trifluoroacetic acid. The reaction mixture wasreduced on a Parr apparatus at 50 psi (3.5 Kg/cm²) hydrogen pressureovernight. The reaction mixture was filtered and washed with methanol toremove the catalyst, and the filtrate was concentrated under vacuum. Theresidue was combined with dichloromethane and aqueous sodium bicarbonatewas added until the mixture was basic. The dichloromethane layer wasseparated, and the aqueous layer was extracted three times withdichloromethane (100 mL). The combined dichloromethane extracts weredried over magnesium sulfate and concentrated under vacuum. Theresulting residue was recrystallized from toluene to provide6,7,8,9-tetrahydro-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amineas a solid, m.p. 226-230° C. Analysis: Calculated for C₁₄H₂₁N₅+1.75H₂O:% C, 57.81; % H, 8.49; % N, 24.07; Found: % C, 57.89; % H, 8.04; % N,23.45.

EXAMPLE 27 Compound of Formula I2-Butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine

[0266]

[0267] Part A:

[0268] Valeryl chloride (0.76 mL, 6.4 mmol) was added to a solution ofN⁵-(2-methylpropyl)tetrazolo[1,5-a][1,7]naphthyridin-4,5-diamine (1.5 g,5.8 mmol) in acetonitrile (15 mL). The reaction mixture was allowed tostir at ambient temperature for several hours. The resulting precipitatewas isolated by filtration. Thin layer chromatography indicated that thematerial contained two components. The solid was dissolved in aceticacid and heated at reflux overnight. The reaction mixture wasconcentrated under vacuum, and the residue extracted withdichloromethane. The dichloromethane extract was washed with water,dried over magnesium sulfate and concentrated under vacuum to provide amixture of2-butyl-1-(2-methylpropyl)-1H-tetrazolo[1,5-a]imidazo[4,5-c][1,7]naphthyridineand the acylated, but uncyclized intermediate.

[0269] Part B:

[0270] Triphenylphosphine (2.4 g) was added to a suspension of thematerial from Part A in dichlorobenzenre. The reaction mixture washeated at reflux overnight then concentrated under vacuum. The residuewas slurried with hexane and the resulting solid2-butyl-1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,7]naphthyridin-4-aminewas isolated by filtration.

[0271] Part C:

[0272] The2-butyl-1-(2-methylpropyl)-N-triphenylphosphinyl-1H-imidazo[4,5-c][1,7]naphthyridin-4-aminefrom Part B was dissolved in methanol. Hydrochloric acid (3N) was addedto the solution and the reaction mixture was heated at reflux overnightbefore being concentrated under vacuum to remove the methanol. Theaqueous residue was mixed with dichloromethane then neutralized withaqueous sodium bicarbonate. The dichloromethane layer was separated,dried over magnesium sulfate and concentrated under vacuum. The residuewas purified by flash chromatography (silica gel eluting withdichloromethane and gradually increasing the polarity to 5% methanol indichloromethane) to provide2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine asa solid, m.p 213-214° C. Analysis: Calculated for C₁₇H₂₃N₅: % C, 68.66;% H, 7.80; % N, 23.55; Found: % C, 68.26; % H, 7.69; % N, 23.41.

EXAMPLE 28 Compound of Formula II2-Butyl-6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine

[0273]

[0274] A catalytic amount of platinum oxide was added to a solution of2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine(0.5 g, 1.68 mol)) in trifluoroacetic acid (20 mL). The reaction mixturewas reduced on a Parr apparatus at 50 psi (3.5 Kg/cm²) hydrogen pressureovernight. The reaction mixture was filtered and washed with methanol toremove the catalyst. The filtrate was concentrated under vacuum. Theresidue was combined with dichloromethane and aqueous sodium bicarbonatewas added until the mixture was basic. The dichloromethane layer wasseparated. The aqueous layer was extracted three times withdichloromethane (100 mL). The dichloromethane extracts were combined,dried over magnesium sulfate and concentrated under vacuum. Theresulting residue was recrystallized from toluene then purified by flashchromatography (silica gel eluting with 20% methanol in dichloromethanewith a trace of ammonium hydroxide) to provide6,7,8,9-tetrahydro-2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amineas a solid, m.p. 164-166° C. Analysis: Calculated for C₁₇H₂₇N₅+0.5H₂O: %C, 65.77; % H, 9.09; % N, 22.56; Found: % C, 65.99; % H, 8.71; % N,22.23.

EXAMPLE 29 Compound of Formula XXXIN⁴-(2-Methylpropyl)-3-nitro[1,5]naphthyridin-4-amine

[0275] Phosphorous oxychloride (0.6 mL, 6.44 mmol) was reacted withN,N-dimethylformamide then added to a solution of3-nitro[1,5]naphthyridin-4-ol (1.0 g, 5.23 mmol) inN,N-dimethylformamide (20 mL). The reaction mixture was warmed using ajacketed flask with refluxing acetone as a heat source. After 3 hoursthe reaction mixture was poured into ice water, isobutylamine (2.0 mL,20.1 mmol) was added and the mixture was heated on a steam bath. Afterseveral hours the reaction mixture was cooled to ambient temperature,filtered and washed with water. The aqueous layer was extracted withdichloromethane. The dichloromethane extract was washed with aqueoussodium bicarbonate, washed with water, dried over magnesium filtratethen loaded onto a layer of silica gel. The silica gel was elutedinitially with dichloromethane to remove an impurity then with 5%methanol in dichloromethane to recover the product. The eluant wasconcentrated to dryness to provideN⁴-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine as a solid, m.p.97-99° C.

EXAMPLE 30 Compound of Formula XXXIII1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine

[0276] Part A:

[0277] A catalytic amount of 5% platinum on carbon was added to asolution of N⁴-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (1.0 g,4.1 mmol) in ethyl acetate (50 mL). The reaction mixture was reduced ona Parr apparatus at 50 psi (3.5 Kg/cm²) hydrogen for four hours. Thereaction mixture was filtered to remove the catalyst and the filtratewas concentrated under vacuum to provideN⁴-(2-methylpropyl)[1,5]naphthyridin-3,4-diamine as a crude solid.

[0278] Part B:

[0279] The crude solid from Part A was combined withdiethoxymethylacetate (2 mL) then heated on a steam bath overnight. Thereaction mixture was taken up in dichloromethane, washed with water,dried over magnesium sulfate then filtered through a layer of silicagel. The silica gel was eluted with dichloromethane to remove excessdiethoxymethylacetate then with 5% methanol in dichloromethane torecover the product. The eluant was concentrated to provide an oil whichwas purified by flash chromatography (silica gel eluting with 50% ethylacetate/hexane then with ethyl acetate) to provide 0.25 g of1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine as a solid m.p.82-84° C. Analysis: Calculated for C₁₃H₁₄N₄: % C, 69.00; % H, 6.24; % N,24.76; Found: % C, 68.79; % H, 6.44; % N, 24.73.

EXAMPLE 31 Compound of Formula XXXIV1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

[0280] 3-Chloroperoxybenzoic acid (3.7 g of 50%) was added in smallportions over a period of 30 minutes to a solution of1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine (1.5 g) inchloroform at ambient temperature. After 3 hours the reaction mixturewas diluted with chloroform, washed twice with 2.0 M sodium hydroxideand once with water, dried over magnesium sulfate then concentratedunder vacuum. The residue was recrystallized from ethyl acetate/hexaneto provide 1.2 g of1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide as asolid, m.p. 183-185° C. Analysis: Calculated for C₁₃H₁₄N₄O: % C, 64.45;% H, 5.82; % N, 23.12; Found: % C, 64.15; % H, 5.92; % N, 23.02.

EXAMPLE 32 Compound of Formula I1-(2-Methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine

[0281]

[0282] Ammonium hydroxide (10 mL) was added to a solution of1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide (0.6 g)in dichloromethane (30 mL). The reaction mixture was cooled in an icebath then tosyl chloride (0.5 g) in dichloromethane was added while thereaction was being rapidly stirred. The reaction mixture was stirred atambient temperature overnight. The dichloromethane layer was separated,washed with aqueous sodium bicarbonate, dried over magnesium sulfatethen concentrated under vacuum. The residue was recrystallized fromethyl acetate/hexane to provide 0.2 g of1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine as asolid, m.p. 230-231.5° C. Analysis: Calculated for C₁₃H₁₅N₅: % C, 64.71;% H, 6.27; % N, 29.02; Found: % C, 64.70; % H, 6.01; % N, 29.08.

EXAMPLE 33 Compound of Formula II6,7,8,9-Tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine

[0283]

[0284] A catalytic amount of platinum oxide was added to a solution of1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine (0.46 g)in trifluoroacetic acid (10 mL). The reaction mixture was reduced on aParr apparatus under 45 psi (3.15 Kg/cm²) hydrogen pressure for 4 hours.The reaction mixture was filtered to remove the catalyst and thefiltrate was concentrated under vacuum. The residue was combined withaqueous sodium bicarbonate then a small amount of 10% sodium hydroxidewas added. The resulting precipitate was extracted with dichloromethane.The dichloromethane extract was dried over magnesium sulfate thenconcentrated under vacuum. The residue was purified by flashchromatography (silica gel eluting with 5% methanol in dichloromethanecontaining 0.5% ammonium hydroxide). The eluant was concentrated undervacuum. The residue was recrystallized from ethyl acetate to provide6,7,8,9-tetrahydro-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amineas a solid, m.p. 222-226° C. Analysis: Calculated for C₁₃H₁₉N₅: % C,63.65; % H, 7.81; % N, 28.55; Found: % C, 63.07; % H, 7.51; % N, 28.00.

EXAMPLE 34 Compound of Formula XXXIII2-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine

[0285] Part A:

[0286] Magnesium sulfate (3 g) and a catalytic amount of 5% platinum oncarbon were added to a solution ofN⁴-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (4.0 g, 16.2 mmol)in ethyl acetate (250 mL). The reaction mixture was reduced on a Parrapparatus at 50 psi (3.5 Kg/cm²) hydrogen for four hours. The reactionmixture was filtered to remove the catalyst and the filtrate wasconcentrated under vacuum to provideN⁴-(2-methylpropyl)[1,5]naphthyridin-3,4-diamine as a crude solid.

[0287] Part B:

[0288] The crude solid from. Part A was taken up in acetic acid,combined with acetic anhydride then heated at reflux overnight. Thereaction mixture was concentrated under vacuum. The resulting residuewas combined with methanol to decompose excess acetic anhydride thenconcentrated under vacuum. The resulting residue was combined withcyclohexane then concentrated under vacuum to remove the acetic acid.The resulting residue was recrystallized from hexanes to provide 2.2 gof 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine asoff-white needles, m.p. 118-119° C. Analysis: Calculated for C₁₄H₁₆N₄: %C, 69.97; % H, 6.71; % N, 23.31; Found: % C, 69.24; % H, 6.67; % N,23.23.

EXAMPLE 35 Compound of Formula XXXIV2-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

[0289] 3-Chloroperoxybenzoic acid (4.5 g of 50%, 13.1 mmol) was added insmall portions over a period of 30 minutes to a solution of2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine (2.1 g,8.7 mmole) in chloroform at ambient temperature. After 3 hours thereaction mixture was diluted with chloroform, washed twice with 2.0 Msodium hydroxide, once with water, and once with brine, dried overmagnesium sulfate then concentrated under vacuum. The residue waspurified by flash chromatography (silica gel eluting with 5% methanol indichloromethane) to provide2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxideas a solid, m.p. 228-230° C. Analysis: Calculated for C₁₄H₁₆N₄O: % C,65.61; % H, 6.29; % N, 21.86; Found: % C, 65.73; % H, 6.31; % N, 21.95.

EXAMPLE 36 Compound of Formula I2-Methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine

[0290]

[0291] Ammonium hydroxide (10 mL) was added to a solution of2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide(1.1 g, 4.29 mmol) in dichloromethane (50 mL). The reaction mixture wascooled in an ice bath then tosyl chloride (0.82 g, 4.29 mmol) indichloromethane was added. The reaction was warmed to about 30° C. whilebeing rapidly stirred. The reaction mixture was stirred at ambienttemperature overnight. The dichloromethane layer was separated, washedwith 10% sodium hydroxide, water and brine, dried over magnesium sulfatethen concentrated under vacuum. The residue was recrystallized fromethyl acetate to provide 0.8 g of2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amineas a solid, m.p. 228-230° C. Analysis: Calculated for C₁₄H₁₇N₅: % C,65.86; % H, 6.71; % N, 27.43; Found: % C, 65.65; % H, 6.69; % N, 27.59.

EXAMPLE 37 Compound of Formula XXXIII2-Butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine

[0292] Part A:

[0293] Magnesium sulfate (3 g) and a catalytic amount of 5% platinum oncarbon were added to a solution ofN⁴-(2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (3.0 g, 12.2 mmol)in ethyl acetate (150 mL). The reaction mixture was reduced on a Parrapparatus at 50 psi (3.5 Kg/cm²) hydrogen for four hours. The reactionmixture was filtered to remove the catalyst and the filtrate wasconcentrated under vacuum to provideN⁴-(2-methylpropyl)[1,5]naphthyridin-3,4-diamine as a crude solid.

[0294] Part B:

[0295] The crude solid from Part A was taken up in acetonitrile thencombined with valeryl chloride (1.5 mL, 12.2 mmol). The mixture wasstirred at ambient temperature for 30 minutes. The resulting precipitatewas isolated by filtration, washed with a small amount of acetonitrileand air dried to provide 2.75 g ofN-(4-(2-methylpropylamino)[1,5]naphthyridin-3-yl)valeramidehydrochloride as a solid.

[0296] Part C:

[0297] The solid from Part B was suspended in acetic acid and heated atreflux overnight. The reaction mixture was concentrated under vacuum andthe resulting residue was partitioned between dichloromethane andaqueous sodium bicarbonate. The dichloromethane layer was separated,dried over magnesium sulfate and concentrated under vacuum to provide2.3 g of 2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridineas an oil.

EXAMPLE 38 Compound of Formula XXXIV2-Butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

[0298] 3-Chloroperoxybenzoic acid (5.3 g of 50%, 15.2 mmol) was added insmall portions over a period of 30 minutes to a solution of2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine (2.3 g,10.2 mmole) in chloroform at ambient temperature. After 3 hours thereaction mixture was diluted with chloroform, washed twice with 2.0 Msodium hydroxide, once with water, and once with brine, dried overmagnesium sulfate then concentrated under vacuum. The residue waspurified by flash chromatography (silica gel eluting with 5% methanol indichloromethane) to provide2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide.Analysis: Calculated for C₁₇H₂₂N₄O: % C, 68.43; % H, 7.43; % N, 18.78;Found: % C, 67.67; % H, 6.73; % N, 18.13

Example 39 Compound of Formula I2-Butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine

[0299]

[0300] Ammonium hydroxide (25 mL) was added to a solution of2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide(2.0 g, 6.7 mmol) in dichloromethane (100 mL). The reaction mixture wascooled in an ice bath then tosyl chloride (1.3 g, 6.7 mmol) indichloromethane was added. The reaction was warmed to about 30° C. whilebeing rapidly stirred. The reaction mixture was stirred at ambienttemperature overnight. The dichloromethane layer was separated, washedwith 10% sodium hydroxide, water and brine, dried over magnesium sulfatethen concentrated under vacuum. The residue was recrystallized fromhexane to provide 1.55 g of2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine asa solid, m.p. 115-116° C. Analysis: Calculated for C₁₇H₂₃N₅: % C, 68.66;% H, 7.80; % N, 23.55; Found: % C, 69.52; % H, 7.72; % N, 21.72

Example 40 Compound of Formula II6,7,8,9-Tetrahydro-2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine

[0301]

[0302] A catalytic amount of platinum oxide was added to a solution of2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine(0.5 g) in trifluoroacetic acid 2) (15 mL). The reaction mixture wasreduced on a Parr apparatus under 50 psi (3.5 Kg/cm²) hydrogen pressureovernight. The reaction mixture was filtered to remove the catalyst andthe filtrate was concentrated under vacuum. The residue was combinedwith aqueous sodium bicarbonate then a small amount of 10% sodiumhydroxide was added. The resulting precipitate was extracted withdichloromethane. The dichloromethane extract was dried over magnesiumsulfate then concentrated under vacuum. The residue was purified byflash chromatography (silica gel eluting with 1-5% methanol indichloromethane containing 0.5% ammonium hydroxide). The eluant wasconcentrated under vacuum. The residue was recrystallized fromhexane/ethyl acetate to provide6,7,8,9-tetrahydro-2-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amineas a solid, m.p. 143-147° C. Analysis: Calculated for C₁₇H₂₇N₅: % C,67.74; % H, 9.03; % N, 23.23; Found: % C, 61.90; % H, 7.51; % N, 19.91.

EXAMPLE 41 Compound of Formula XXXI 1,1-DimethylethylN-{4-[(3-Nitro[1,5]naphthyridin-4-yl)amino]butyl}carbamate

[0303] Phosphorus oxychloride (4 mL, 0.31 mole) was combined withN,N-dimethylformamide (100 mL) while cooling in an ice bath. Theresulting mixture was added to a solution of3-nitro[1,5]naphthyridin-4-ol (50 g, 0.26 mole) in N,N-dimethylformamide(500 mL). The reaction mixture was stirred at ambient temperature for 6hours. The reaction mixture was poured into ice water and then extractedwith dichloromethane (1800 mL). The organic layer was separated and thencombined with triethylamine (45 mL). Tert-butylN-(4-aminobutyl)carbamate was added and the reaction mixture was stirredovernight. The reaction mixture was concentrated under vacuum and theresidue was treated with water (˜500 mL). The resulting solid wasisolated by filtration, washed with water and dried to provide 76 g of1,1-dimethylethylN-{4-[(3-nitro[1,5]naphthyridin-4-yl)amino]butyl}carbamate as a solid. Asmall sample was recrystallized from isopropyl alcohol to provide a puresample, m.p. 137-138° C. Analysis: Calculated for C₁₇H₂₃N₅O₄: % C,56.50; % H, 6.41; % N, 19.38; Found: % C, 56.26; % H, 6.30; % N, 19.53.

EXAMPLE 42 Compound of Formula XXXII 1,1-DimethylethylN-{4-[(3-Amino[1,5]naphthyridin-4-yl)amino]butyl}carbamate

[0304] 1,1-DimethylethylN-{4-[(3-nitro[1,5]naphthyridin-4-yl)amino]butyl}carbamate (42.7 g, 0.12mole), platinum on carbon (2 g) and ethyl acetate (500 mL) were combinedand then hydrogenated on a Parr apparatus at 30 psi (2.1 Kg/cm²)hydrogen pressure for 1 hour. The catalyst was removed by filtration andrinsed with ethyl acetate. The filtrate was concentrated under vacuum toprovide 1,1-dimethylethylN-{4-[(3-amino[1,5]naphthyridin-4-yl)amino]butyl}carbamate as a brightyellow-orange solid.

EXAMPLE 43 Compound of Formula XXXIII 1,1-DimethylethylN-[4-(2-Butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate

[0305] Freshly distilled trimethyl orthovalerate (41 mL, 0.24 mole) wasadded to a mixture of 1,1-dimethylethylN-{4-[(3-amino[1,5]naphthyridin-4-yl)amino]butyl}carbamate (39 g, 0.12mole) in warm xylene (500 mL). The reaction mixture was heated at refluxovernight. Thin layer chromatography showed that at least half of thestarting material was still present. p-Toluenesulfonic anhydridemonohydrate (6 g) was added. After a short time thin layerchromatography showed that the reaction was complete. The reactionmixture was allowed to cool to ambient temperature and then it wasdiluted with ethyl acetate and washed with aqueous sodium bicarbonate.The organic layer was concentrated under vacuum to provide an oilyresidue. The residue was triturated with hexane to provide a dark pinksolid. This solid was recrystallized from acetonitrile to provide1,1-dimethylethylN-[4-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate asa pale peach solid, m.p. 96.0-98.0° C. Analysis: Calculated forC₂₂H₃₁N₅O₂: % C, 66.47; % H, 7.86; % N, 17.62; Found: % C, 66.29; % H,7.78; % N, 17.76.

EXAMPLE 44 Compound of Formula XXXIV1-{4-[(1,1-Dimethylethylcarbonyl)amino]butyl}-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

[0306] 3-Chloroperbenzoic acid (1 eq at 57%) was added in portions to asolution of 1,1-dimethylethylN-[4-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate inchloroform (50 mL). The reaction mixture was allowed to stir at ambienttemperature for 2 hours at which time thin layer chromatography showedthat no starting material remained. The reaction mixture was dilutedwith dichloromethane and then washed twice with 1M sodium hydroxide. Theorganic layer was dried over anhydrous magnesium sulfate and thenconcentrated under vacuum to provide1-{4-[(1,1-dimethylethylcarbonyl)amino]butyl}-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxideas an orange oil which solidified on standing.

EXAMPLE 45 Compound of Formula I 1,1-DimethylethylN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate

[0307]

[0308] Ammonium hydroxide (20 mL) was added to a solution of1-{4-[(1,1-dimethylethylcarbonyl)amino]butyl}-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide(19.4 g) in chloroform. Tosyl chloride (9 g) was slowly added. Thinlayer chromatography indicated that the reaction was proceeding slowly.Additional tosyl chloride was added twice. After thin layerchromatography indicated that the reaction was complete, the layers wereseparated. The organic layer was washed with dilute aqueous sodiumcarbonate, dried over magnesium sulfate and then concentrated undervacuum. The residue was covered with methyl acetate (10 mL), hexane (5mL) was added and the mixture was allowed to stand overnight. Theresulting crystalline solid was isolated by filtration, washed withhexane and then dried to provide 15.1 g of 1,1-dimethylethylN-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate,m.p. 148.5-149.5° C. Analysis: Calculated for C₂₂H₃₂N₆O₂: % C, 64.05; %H, 7.82; % N, 20.37; Found: % C, 64.15; % H, 7.82; % N, 20.55.

EXAMPLE 46 Compound of Formula I4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine

[0309]

[0310] A suspension of 1,1-dimethylethylN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate(13.8 g) in 1N hydrochloric acid (140 mL) was heated on a steam bath for1.5 hours. The reaction mixture was allowed to cool to ambienttemperature and then it was made basic (pH>11) with 50% sodiumhydroxide. The resulting precipitate was isolated by filtration, washedwith water and then dried to provide 9.5 g of4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamineas a white solid, m.p. 212-213° C. Analysis: Calculated for C₁₇H₂₄N₆: %C, 65.36; % H, 7.74; % N, 26.90; Found: % C, 65.16; % H, 7.65; % N,27.29.

Example 47 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-phenylurea

[0311]

[0312] Under a nitrogen atmosphere, phenyl isocyanate (52 μL, 0.48 mmol)was added to a suspension of4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.15 g, 0.48 mmole) in anhydrous tetrahydrofuran (60 mL). The reactionmixture was stirred for 20 minutes at which time it had turnedhomogeneous and thin layer chromatography indicated no starting materialremained. Aminomethyl resin (280 mg of 1% cross linked, 100-200 meshavailable from BACHEM, Torrance, Calif.) was added and the reactionmixture was allowed to stir for 0.5 hr. Silica gel (0.4 g) was added andthe mixture was concentrated under vacuum to provide a solid. The solidwas purified by flash chromatography eluting with 95/5dichloromethane/methanol to give a white solid which was dried undervacuum at 60° C. to provide 0.12 g ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-phenylurea.Analysis: Calculated for C₂₄H₂₉N₇O+⅕H₂O: % C, 66.25; % H, 6.81; % N,22.53; Found: % C, 66.27; % H, 6.63; % N, 22.83

Example 48 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-cyclohexylurea

[0313]

[0314] Using the general method of Example 47, cyclohexyl isocyanate (61μL, 0.48 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.15 g, 0.48 mmole) to provide 0.14 g ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-cyclohexylureaas a white solid. Analysis: Calculated for C₂₄H₃₅N₇O: % C, 65.88; % H,8.06; % N, 22.41. ¹H NMR (300 MHz, CDCl₃) δ 8.60 (dd, J=4.4, 1.4 Hz,1H), 8.08 (d, J=8.5 Hz, 1H), 7.44 (dd, J=8.5, 4.4 Hz, 1H), 5.55 (br s,2H), 4.92 (t, J=5.8 Hz, 1H), 4.82 (apparent t, J=7.8 Hz, 2H), 4.13 (d,J=8.6 Hz, 1H), 3.48 (m, 1H), 3.35 (apparent q, J=6.4 Hz, 2H), 2.93(apparent t, J=7.8 Hz, 2H), 1.80-2.05 (m, 4H), 1.45-1.75 (m, 6H),1.2-1.4 (m 2H), 1.0-1.2 (m, 2 H), 1.03 (t, 7.4 Hz, 3H); HRMS (EI) calcdfor C₂₄H₃₅N₇O (M⁺) 437.2903, found 437.2903.

EXAMPLE 49 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-butylurea

[0315]

[0316] Using the general method of Example 47, butyl isocyanate (54 μL,0.48 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.15 g, 0.48 mmole) to provide 0.13 g ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-butylureaas a white solid. Analysis: Calculated for C₂₂H₃₃N₇O: % C, 64.21; % H,8.08; % N, 23.82; Found: % C, 64.05; % H, 7.97; % N, 24.00.

EXAMPLE 50 Compound of Formula I PhenylN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate

[0317]

[0318] Using the general method of Example 47, phenyl chloroformate (61μL, 0.48 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.15 g, 0.48 mmole) to provide 0.12 g of phenylN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamateas a solid. Analysis: Calculated for C₂₄H₂₈N₆O₂: % C, 66.65; % H, 6.53;% N, 19.43; Found: % C, 66.49; % H, 6.59; % N, 19.32.

EXAMPLE 51 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-furamide

[0319]

[0320] Using the general method of Example 47, furoyl chloride (15.8 μL,0.16 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.05 g, 0.16 mmole) to provide 0.019 g ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-furamideas a white solid. ¹H NMR (300 MHz, CDCl₃) δ 8.58 (dd, 3=4.4, 1.5 Hz,1H), 8.06 (dd, J=8.6, 1.6 Hz, 1H), 7.41 (dd, J=8.5, 4.4 Hz, 1H), 7.33(m, 1H), 7.08 (dd, J=3.5, 0.6 Hz, 1H), 6.84 (m, 1H), 6.47 (dd, J=3.5,1.7 Hz, 1H), 4.86 (apparent t, J=7.7 Hz, 2H), 3.59 (apparent q, J=6.5Hz, 2H), 2.92 (apparent t, J=7.8 Hz, 2H), 1.7-2.1(m, 6H), 1.51 (m, 2H);1.00 (t, J=7.3 Hz, 3H); HRMS (EI) calcd for C₂₂H₂₆N₆O₂ (M⁺) 406.2117,found 406.2121.

EXAMPLE 52 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]benzamide

[0321]

[0322] Using the general method of Example 47, benzoyl chloride (56 μL,0.48 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.15 g, 0.48 mmole) to provide 0.11 g ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]benzamideas a white solid. Analysis: Calculated for C₂₄H₂₈N₆O+/4H₂O: % C, 68.47;% H, 6.82; % N, 19.96: Found: % C, 68.24; % H, 6.76; % N, 19.90.

EXAMPLE 53 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-benzylurea

[0323]

[0324] Benzyl isocyanate (59 μL, 0.48 mmol) was added at ambienttemperature to a suspension of4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.15 g, 0.48 mmol) in tetrahydrofuran (60 mL). A solution was obtainedin less than 30 minutes and thin layer chromatography (9:1dichloromethane:methanol) showed one major new spot with a higher R_(f)and only a trace of starting material. Aminomethyl resin (280 mg) wasadded and the reaction mixture was stirred for 15 minutes. The solventwas removed under vacuum. The residue was purified by columnchromatography to provide 0.16 g ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-N′-benzylureaas a white solid. Analysis: Calculated for C₂₅H₃₁N₇O: % C, 67.39; % H,7.01; % N, 22.00; Found: % C, 67.43; % H, 6.92; % N, 22.02.

EXAMPLE 54 Compound of Formula IN³-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]nicotinamide

[0325]

[0326]4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.050 g, 0.16 mmol) was suspended in tetrahydrofuran (30 mL).N,N-diisopropylethylamine (28 μL, 0.16 mmol) was added to the suspensionand then nicotinoyl chloride hydrochloride (0.028 g, 0.16 mmol) wasadded. The reaction mixture was stirred at ambient temperature for 1hour by which time a solution was obtained. Thin layer chromatography(9:1 dichloromethane:methanol) showed one major new spot with a higherR_(f) and only a trace of starting material. Aminomethyl resin (100 mg)was added and the reaction mixture was stirred for 5 minutes. Thesolvent was removed under vacuum. The residue was dissolved indichloromethane and placed on a layer of silica gel. The silica gel waseluted first with dichloromethane and then with 9:1dichloromethane:methanol. The cleanest fractions were combined and thenconcentrated under vacuum to provideN³-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]nicotinamideas a white powder. ¹H NMR (300 MHz, CDCl₃)™ 8.91 (m, 1H), 8.68 (d, J=4.5Hz, 1H), 8.45 (d, J=4.3 Hz, 1H), 8.03 (m, 2H), 7.30-7.40 (m, 2H), 6.98(s, 2H), 5.51 (s, 1H), 4.86 (apparent t, J=7.9 Hz, 2H), 3.66 (q, J=6.5Hz, 2H), 2.92 (apparent t, J=7.7 Hz, 2H), 2.05 (m, 2H), 1.75-1.95 (m,4H), 1.51 (m, 2H), 1.00 (t, J=7.3 Hz, 3H); HRMS (E) calcd for C₂₃H₂₇N₇O(M⁺) 417.2277, found 417.2276.

EXAMPLE 55 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]phenylaceatamide

[0327]

[0328] Phenylacetyl chloride (21 μL, 0.16 mmol) was added to asuspension of4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.050 g, 0.16 mmol) in tetrahydrofuran (30 mL). The reaction mixturewas stirred at ambient temperature for 1 hour by which time a solutionwas obtained. Thin layer chromatography (9:1 dichloromethane:methanol)showed one major new spot with a higher R_(f) and only a trace ofstarting material. Aminomethyl resin (100 mg) was added and the reactionmixture was stirred for 5 minutes. The solvent was removed under vacuumto provide a white powder. This material was placed on a short column ofsilica gel and purified by eluting first with dichloromethane and thenwith 9:1 dichloromethane:methanol. The cleanest fractions were combinedand then concentrated under vacuum to provide a colorless oil. The oilwas dissolved in dichloromethane, hexane was added just until thesolution started to become cloudy, and then the solvent was removed toprovideN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]phenylacetamideas a white powder. Analysis: Calculated for C₂₅H₃₀N₆O₂: % C, 67.24; % H,6.77; % N, 18.82; Found: % C, 67.52; % H, 6.85; % N, 18.38. ¹H NMR (300MHz, CDCl₃) T 8.51 (dd, J=4.4, 1.5 Hz, 1H), 8.11 (dd, J=8.4, 1.4 Hz,1H), 7.43 (dd, J=8.4, 4.4 Hz, 1H), 7.10-7.20 (m, 5H), 6.30 (br s, 2H),5.83 (m, 1H), 4.72 (apparent t, J=7.8 Hz, 2H), 3.54 (s, 2H), 3.35(apparent q, J=6.5 Hz, 2H), 2.88 (apparent t, J=7.8 Hz, 2H), 1.80-1.90(m, 4H), 1.45-1.65 (m, 4H), 1.00 (t, J=7.3 Hz, 3H); HRMS (EI) calcd forC₂₅H₃₀N₆O (M⁺) 430.2481, found 430.2490.

EXAMPLE 56 Compound of Formula I BenzylN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate

[0329]

[0330] Using the general method of Example 55, benzyl chloroformate (83μL, 0.58 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.15 g, 0.48 mmol) to provide 0.18 g of benzylN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamateas a white powder.

EXAMPLE 57 Compound of Formula I 9H-9-FluorenylmethylN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate

[0331]

[0332] Using the general method of Example 55, 9-fluorenylmethylchloroformate (0.085 g, 0.33 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.105 g, 0.33 mmol) to provide 0.125 g of 9H-9-fluorenylmethylN-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamateas a white powder. Analysis: Calculated for C₃₂H₃₄N₆O₂+¼H₂O: % C, 71.29;% H, 6.45; % N, 15.59; Found: % C, 70.99; % H, 6.35; % N, 15.55.

EXAMPLE 58 Compound of Formula I EthylN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate

[0333]

[0334] Using the general method of Example 55, ethyl chloroformate (46μL, 0.48 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.15 g, 0.48 mmol) to provide 0.15 g of ethylN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamateas a white powder. Analysis: Calculated for C₂₀H₂₈N₆O₂: % C, 62.48; % H,7.34; % N, 21.86; Found: % C, 61.73; % H, 7.28; % N, 21.62.

EXAMPLE 59 Compound of Formula XXXI1,1-Dimethyl-2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethanol

[0335] Phosphorus oxychloride (4 mL, 43 mmol) was reacted withN,N-dimethylformamide (15 mL) while chilling in an ice bath. Thismixture was added to a solution of 3-nitro[1,5]naphthyridin-4-ol (6.9 g,36.1 mmol) in N,N-dimethylformamide (60 mL). The reaction mixture waswarmed in an oil bath to 60° C. After 3 hours the reaction mixture waspoured into ice water. The resulting precipitate was isolated byfiltration and then washed with water. The wet crude5-chloro-3-nitro[1,5]naphthyridine was suspended in dichloromethane (150mL). Diisopropylethylamine was added followed by the slow addition ofhydroxyisobutylamine (3.4 g, 40 mmol). The reaction mixture was refluxedfor 2 hours and then combined with water (˜100 mL). The resultingprecipitate was isolated by filtration to provide 7.2 g of1,1-dimethyl-2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethanol. A smallsample was recrystallized from isopropanol to provide a pure sample,m.p. 184.5-186° C. Analysis: Calculated for C₁₂H₁₄N₄O₃: % C, 54.96; % H,5.38; % N, 21.36; Found: % C, 54.63; % H, 5.36: % N, 21.51.

EXAMPLE 60 Compound of Formula XXXIII1,1-Dimethyl-2-(2-butyl[1,5]napthyridin-1-yl)ethanol

[0336] Part A

[0337] A catalytic amount of 5% platinum on carbon was added to asuspension of1,1-dimethyl-2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethanol (7 g, 26mmol) in isopropanol (300 mL). The mixture was hydrogenated on a Parrapparatus at 50 psi (3.5 Kg/cm²) hydrogen pressure for 3 hours. Thereaction mixture was fileted to remove the catalyst. The filtrate wasconcentrated under vacuum. Toluene was added to the residue and themixture was concentrated under vacuum to remove all of the alcohol andprovidecrude1,1-dimethyl-2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethanol.

[0338] Part B

[0339] Trimethylorthovalerate (3.6 mL, 20 mmol) was added to asuspension of1,1-dimethyl-2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethanol 3.5 g, 13mmol) in xylene (100 mL). The reaction mixture was heated at reflux fortwo days. The mixture was diluted with methanolic ammonia, placed in aParr vessel and then heated at 110° C. for 4 hours. The reaction mixturewas concentrated under vacuum. The residue was partitioned betweendichloromethane and water. The layers were separated. The organic layerwas washed with water, dried over magnesium sulfate and thenconcentrated under vacuum to provide an oil. The oil was recrystallizedfrom methyl acetate/benzene to provide 2.8 g of1,1-dimethyl-2-(2-butyl[1,5]napthyridin-1-yl)ethanol as a solid, m.p.85-88.5° C. Analysis: Calculated for C₁₇H₂₂N₄O: % C, 68.43; % H, 7.43; %N, 18.78; Found: % C, 68.04; % H, 7.18; % N, 19.09.

EXAMPLE 61 Compound of Formula XXXIV2-Butyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

[0340] 3-Chloroperbenzoic acid (2.6 g, 9.5 mmol) was added in 3 portionsto a solution of 1,1-dimethyl-2-(2-butyl[1,5]napthyridin-1-yl)ethanol(2.6 g, 8.7 mmol) in chloroform (50 mL) in a flask covered with aluminumfoil. The reaction mixture was stirred at ambient temperature for 4hours; then it was washed twice with dilute aqueous sodium bicarbonate,washed with brine, dried over magnesium sulfate and then concentratedunder vacuum. The residue was recrystallized from methyl acetate toprovide 2.25 g of2-butyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide,m.p. 156-158° C. Analysis: Calculated for: C₁₇H₂₂N₄O₂+¼H₂O: % C, 64.03;% H, 7.11; % N, 17.57; Found: % C, 63.96; % H, 6.84; % N, 17.71.

EXAMPLE 62 Compound of Formula I1,1-Dimethyl-2-(4-amino-2-butyl[1,5]napthyridin-1-yl)ethanol

[0341]

[0342] Ammonium hydroxide (15 mL) was added to a solution of2-butyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide(1.9 g, 6.0 mmol) in dichloromethane (40 mL). Tosyl chloride (1.2 g, 6.4mmol) was slowly added. Thin layer chromatography indicated that thereaction was proceeding slowly. Additional tosyl chloride was addedtwice. After thin layer chromatography indicated that the reaction wascomplete, the layers were separated. The organic layer was washed withdilute aqueous sodium carbonate, dried over magnesium sulfate and thenconcentrated under vacuum. The residue was covered with methyl acetate(10 mL), hexane (5 mL) was added and the mixture was allowed to standovernight. The resulting crystalline solid was isolated by filtration toprovide 0.9 g of1,1-dimethyl-2-(4-amino-2-butyl[1,5]napthyridin-1-yl)ethanol, m.p.177-179° C. Analysis: Calculated for C₁₇H₂₃N₅O: % C, 65.15; % H, 7.40; %N, 22.35; Found: % C, 64.97; % H, 7.33; % N, 22.71.

Example 63 Compound of Formula XXXIII1,1-Dimethyl-2-(2-phenylemethyl[1,5]napthyridin-1-yl)ethanol

[0343] Part A

[0344] Phenylacetyl chloride (2.0 mL, 20 mmol) was added to a suspensionof 1,1-dimethyl-2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethanol 3.5 g,13 mmol) in dichloromethane (100 mL). The reaction mixture was heated atreflux until thin layer chromatography indicated that the reaction wascomplete. The reaction mixture was taken on to the next step.

[0345] Part B

[0346] The material from Part A was combined with 7% ammonia in methanol(100 mL), placed in a sealed vessel, and then heated at 150° C. for 6hours. The reaction mixture was concentrated under vacuum. The residuewas combined with water (100 mL) and then extracted with dichloromethane(2×75 mL). The extracts were combined, washed with water (100 mL), driedover magnesium sulfate and then concentrated under vacuum. The residuewas recrystallized from methyl acetate to provide 2.1 g of1,1-dimethyl-2-(2-phenylmethyl[1,5]napthyridin-1-yl)ethanol as a solid,m.p. 150-152° C. Analysis: Calculated for C₂₀H₂₀N₄O: % C, 72.27; % H,6.06; % N, 16.85; Found: % C, 72.11; % H, 6.01; % N, 17.00.

EXAMPLE 64 Compound of Formula XXXIV2-Phenylmethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

[0347] 3-Chloroperbenzoic acid (1.8 g, 6.6 mmol) was added in 3 portionsto a solution of1,1-dimethyl-2-(2-phenylmethyl[1,5]napthyridin-1-yl)ethanol (2 g, 6mmol) in chloroform (50 mL) in a flask covered with aluminum foil. Thereaction mixture was stirred at ambient temperature overnight; then itwas washed twice with dilute aqueous sodium bicarbonate, washed withbrine, dried over magnesium sulfate and then concentrated under vacuum.The residue was recrystallized from isopropanol to provide 2.25 g of2-phenylmethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide,m.p. 204-206° C. Analysis: Calculated for: C₂₀H₂₀N₄O₂+½H₂O: % C, 67.21;% H, 5.92; % N, 15.68; Found: % C, 67.05; % H, 5.65; % N, 15.39.

EXAMPLE 65 Compound of Formula I1,1-Dimethyl-2-(4-amino-2-phenylmethyl[1,5]napthyridin-1-yl)ethanol

[0348]

[0349] Ammonium hydroxide (10 mL) was added to a solution of2-phenylmethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide(1.5 g, 4.3 mmol) in dichloromethane (40 mL). Tosyl chloride (0.8 g, 4.3mmol) was slowly added. Thin layer chromatography indicated that thereaction was proceeding slowly. Additional tosyl chloride was addedtwice. After thin layer chromatography indicated that the reaction wascomplete, the layers were separated. The organic layer was washed withdilute aqueous sodium carbonate, dried over magnesium sulfate and thenconcentrated under vacuum. The residue was covered with methyl acetate(10 mL), hexane (5 mL) was added and the mixture was allowed to standovernight. The resulting crystalline solid was isolated by filtration toprovide1,1-dimethyl-2-(4-amino-2-phenylmethyl[1,5]napthyridin-1-yl)ethanol,m.p. 211-213° C. Analysis: Calculated for C₂₀H₂₁N₅O: % C, 69.14; % H,6.09; % N, 20.16; Found: % C, 69.10; % H, 6.12; % N, 20.48.

EXAMPLE 66 Compound of Formula XXXIN-Phenylmethyl-3-nitro[1,5]naphthyridin-4-amine

[0350] Phosphorus oxychloride (3.5 mL, 37.7 mmol) was reacted withN,N-dimethylformamide (15 mL) while chilling in an ice bath. Thismixture was added to a solution of 3-nitro[1,5]naphthyridin-4-ol (6.0 g,31.4 mmol) in N,N-dimethylformamide (60 mL). The reaction mixture waswarmed in an oil bath to 60° C. After 3 hours the reaction mixture waspoured into ice water. The resulting precipitate was isolated byfiltration and then washed with water. The wet crude5-chloro-3-nitro[1,5]naphthyridine was suspended in dichloromethane (150mL). Diisopropylethylamine (1.2 eq) was added followed by the slowaddition of benzylamine (4.7 mL g, 40 mmol). The reaction mixture wasrefluxed for 2 hours and then combined with water (100 mL). The layerswere separated and the organic layer was concentrated under vacuum toprovide 5.5 g of N-phenylmethyl-3-nitro[1,5]naphthyridin-4-amine. Asmall sample was recrystallized from isopropanol to provide a puresample, m.p. 127-129° C. Analysis: Calculated for C₁₅H₁₂N₄O₂: % C,64.28; % H, 4.32; % N, 19.99; Found: % C, 63.89; % H, 4.40: % N, 20.35.

EXAMPLE 67 N-(4-Phenylmethylamino[1,5]naphthyridin-3-yl)-ethoxyacetamideHydrochloride

[0351] A catalytic amount of platinum on carbon was added to asuspension of N-phenylmethyl-3-nitro[1,5]naphthyridin-4-amine (5.1 g,18.2 mmol) in toluene (300 mL). The reaction mixture was hydrogenated ona Parr apparatus under a hydrogen pressure of 50 psi (3.5 Kg/cm²) for 1hour. The reaction mixture was filtered to remove the catalyst. Thefiltrate was concentrated under vacuum to a volume of about 200 mL andthen reacted with ethoxyacetyl chloride (2.5 g, 20 mmol). The resultingyellow precipitate was isolated by filtration, suspended in diethylether, and then isolated by filtration to provide 5.8 g ofN-(4-phenylmethylamino[1,5]naphthyridin-3-yl)ethoxyacetamidehydrochloride, m.p. 205-212° C. Analysis: Calculated for C₁₉H₂₀N₄O₂HCl:% C, 61.21; % H, 5.68; % N, 15.03; Found: % C, 60.90; % H, 5.38; % N,15.38.

EXAMPLE 68 Compound of Formula XXXIII2-Ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridine

[0352] N-(4-Phenylmethylamino[1,5]naphthyridin-3-yl)-ethoxyacetamidehydrochloride (5.8 g, 15.5 mmol) was combined with a 7% solution ofammonia in methanol (100 mL), placed in a sealed Parr vessel and thenheated at 150° C. for 6 hours. The reaction mixture was concentratedunder vacuum. The residue was partitioned between water anddichloromethane. The dichloromethane layer was separated, washed withwater, dried over magnesium sulfate and then concentrated under vacuum.The residue was recrystallized from methyl acetate to provide 4.3 g of2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridine, m.p.11.8-119° C. Analysis: Calculated for C₁₉H₁₈N₄O: % C, 71.68; % H, 5.70;% N, 17.60; Found: % C, 71.44; % H, 5.60; % N, 17.66.

EXAMPLE 69 Compound of Formula XXXIV2-Ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

[0353] 3-Chloroperbenzoic acid (3.7 g, 13.4 mmol) was added in 3portions to a solution of2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridine (3.9g, 12.2 mmol) in chloroform (100 mL) in a flask covered with aluminumfoil. The reaction mixture was stirred at ambient temperature overnight;and then it was washed twice with dilute aqueous sodium bicarbonate andonce with brine. The chloroform layer was divided into two portions. Oneportion was used in the example below. The second portion wasconcentrated under vacuum. The residue was recrystallized from isopropylalcohol to provide2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxideas a solid, m.p. 187.5-189° C. Analysis: Calculated for C₁₉H₁₈N₄O₂+¼H₂O:% C, 67.52; % H, 5.49; % N, 16.58; Found: % C, 67.56; % H, 5.36; % N,16.77.

EXAMPLE 70 Compound of Formula I2-Ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine

[0354]

[0355] Ammonium hydroxide (20 mL) was added to the chloroform solutionof2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxidefrom the example above. Tosyl chloride was slowly added. Thin layerchromatography indicated that the reaction was proceeding slowly.Additional tosyl chloride was added twice. After thin layerchromatography indicated that the reaction was complete, the layers wereseparated. The organic layer was washed with dilute aqueous sodiumcarbonate, dried over magnesium sulfate and then concentrated undervacuum. The residue was covered with methyl acetate (10 mL), hexane (5mL) was added and the mixture was allowed to stand overnight. Theresulting crystalline solid was isolated by filtration to provide2-ethoxymethyl-1-phenylmethyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine,m.p. 173-174° C. Analysis: Calculated for C₁₉H₁₉N₅O: % C, 68.45; % H,5.74; % N, 21.01; Found: % C, 68.35; % H, 5.83; % N, 21.27.

EXAMPLE 71 Compound of Formula XXXIN⁴-(3-Isopropoxypropyl)-3-nitro[1,5]naphthyridin-4-amine

[0356] Part A

[0357] Phosphorus oxychloride (3.4 mL, 30 mmol) was added to chilled(ice bath) N,N-dimethylformamide (15 mL). The resulting solution wasadded dropwise to a solution of 3-nitro[1,5]naphthyridin-4-ol (5.73 g,30 mmol) in N,N-dimethylformamide (35 mL). The reaction mixture wasmaintained at ambient temperature for 5 hours and then it was pouredonto ice. The resulting yellow precipitate was isolated by filtrationand then partitioned between dichloromethane (200 mL) and water (150mL). The organic layer was separated, dried over magnesium sulfate,filtered, and then concentrated under vacuum to provide 4.2 g of crude4-chloro-3-nitro[1,5]naphthyridine.

[0358] Part B

[0359] 4-Chloro-3-nitro[1,5]naphthyridine (4.1 g), dichloromethane (150mL), triethylamine (4.1 mL, 29.5 mmol), and 3-isopropoxypropylamine (3.3mL, 23.8 mmol) were combined. The reaction mixture was maintained atambient temperature overnight and then quenched with water (100 mL). Thephases were separated. The aqueous phase was extracted withdichloromethane (100 mL). The organic phases were combined, dried overmagnesium sulfate, filtered and then concentrated under vacuum toprovide a yellow oil. The oil was purified by flash chromatography(silica gel eluting with 1:1 ethyl acetate:hexanes) to provide 4.8 g ofN⁴-(3-isopropoxypropyl)-3-nitro[1,5]naphthyridin-4-amine as a yellowpowder, m.p. 62.5-63.5° C. Analysis: Calculated for C₁₄H₁₈N₄O₃: % C,57.92; % H, 6.25; % N, 19.30; Found: % C, 57.96; % H, 6.19; % N, 19.51.¹H NMR (300 MHz, CDCl₃): δ 10.08 (broad s, 1H), 9.38 (broad s, 1H), 8.78(m, 1H), 8.21 (dd, J=8.4, 1.6 Hz, 1H), 7.64 (dd, J=8.4, 4.1 Hz, 1H),4.57 (broad s, 2H), 3.65-3.57 (m, 3H), 2.05 (t, J=5.6 Hz, 2H), 1.19 (d,J=6.0 Hz, 6H); MS (EI): m/e 290.1366 (290.1378 calc'd for C₁₄H₁₈N₄O₃).

EXAMPLE 72 Compound of Formula XXXIIN⁴-(3-Isopropoxypropyl)[1,5]naphthyridine-3,4-diamine

[0360] N⁴-(3-Isopropoxypropyl)-3-nitro[1,5]naphthyridin-4-amine (4.2 g,14.5 mmol), platinum on carbon (1.1 g of 5%), and ethyl acetate (100 mL)were placed in a hydrogenation flask. The mixture was shaken under ahydrogen pressure of 50 psi (3.5 Kg/cm²) for 2.5 hours. The reactionmixture was filtered and the catalyst was washed with ethyl acetate. Thefiltrate was dried over magnesium sulfate, filtered and thenconcentrated under vacuum to provide 3.6 g ofN⁴-(3-isopropoxypropyl)[1,5]naphthyridine-3,4-diamine as a bright yellowoil. ¹H NMR (300 MHz, CDCl₃): δ 8.70 (dd, J=4.1, 1.6 Hz, 1H), 8.39 (s,1H), 8.17 (dd, J=8.4, 1.6 Hz, 1H), 7.37 (dd, J=8.4, 4.1 Hz, 1H), 5.99(broad s, 1H), 3.98 (broad s, 2H), 3.63-3.55 (m, 5H), 1.87 (pentet,J=6.2 Hz, 2H), 1.17 (d, J=6.1 Hz, 6H); MS (EI): m/e 260.1.630 (260.1637calc'd for C₁₄H₂₀N₄O).

EXAMPLE 73 Compound of Formula XXXIII2-Butyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridine

[0361] Part A

[0362] Valeryl chloride (1.53 mL, 12.9 mmol) was added dropwise over a15 minute period to a chilled (ice bath) solution ofN⁴-(3-isopropoxypropyl)[1,5]naphthyridine-3,4-diamine (3.2 g, 12.3 mmol)in dichloromethane (40 mL). The cooling bath was removed and thereaction mixture was maintained at ambient temperature for 1 hour. Thesolvent was removed under vacuum to provide a dark tan solid.

[0363] Part B

[0364] The material from Part A and a 7.5% solution of ammonia inmethanol (100 mL) were placed in a pressure vessel. The vessel wassealed and then heated at 150° C. for 6 hours. After the mixture wascooled to ambient temperature it was concentrated under vacuum. Theresidue was partitioned between dichloromethane (150 mL) and water (150mL). The fractions were separated and the aqueous fraction was extractedwith dichloromethane (100 mL). The organic fractions were combined,dried over magnesium sulfate, filtered and then concentrated undervacuum to provide a brown oil. The oil was purified by flashchromatography (silica gel eluting with ethyl acetate) to provide 3.1 gof 2-butyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridine asa colorless oil. ¹H NMR (300 MHz, CDCl₃): δ 9.32 (s, 1H), 8.90 (dd,J=4.3, 1.7 Hz, 1H), 8.49 (dd, J=8.5, 1.7 Hz, 1H), 7.57 (dd, J=8.5, 4.3Hz, 1H), 4.94 (t, J=7.0 Hz, 2H), 3.56 (pentet, J=6.1 Hz, 1H), 3.44 (t,J=5.7 Hz, 2H), 3.05 (t, J=7.9 Hz, 2H), 2.29-2.20 (m, 2H), 2.01-1.90 (m,2H), 1.60-1.48 (m, 2H), 1.15 (d, J=6.1 Hz, 6H), 1.03 (t, J=7.3 Hz, 3H);MS (EI): m/e 326.2104 (326.2106 calc'd for C₁₉H₂₆N₄O).

EXAMPLE 74 Compound of Formula XXXIV2-Butyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

[0365] 3-Chloroperbenzoic acid (1.2 g of 57-86%) was added in fourportions over a period of 20 minutes to2-butyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridine (1.4g, 4.3 mmol) in chloroform (20 mL). The reaction mixture was maintainedat ambient temperature for 2 hours and then it was washed with saturatedsodium bicarbonate (2×15 mL) and water (20 mL). The organic fraction wasdried over magnesium sulfate, filtered and then concentrated undervacuum to provide a yellow oil. The oil was purified by columnchromatography (silica gel eluting with 95:5 ethyl acetate:methanol) toprovide 0.95 g of2-butyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxideas a yellow solid, m.p. 92.0-93.0° C. Analysis: Calculated forC₁₉H₂₆N₄O₂: % C, 66.64; % H, 7.65; % N, 16.36; Found: % C, 66.18; % H,7.39; % N, 16.26. ¹H NMR (300 MHz. CDCl₃): δ 9.24 (dd, J=8.8, 1.6 Hz,1H), 9.05 (s, 1H), 8.98 (dd, J=4.3, 1.6 Hz, 1H), 7.65 (dd, J=8.8, 4.3Hz, 1H), 4.89 (t, J=7.0 Hz, 2H), 3.56 (pentet, J=6.1 Hz, 1H), 3.44 (t,J=5.7 Hz, 2H), 3.02 (t, J=7.9 Hz, 2H), 2.27-2.18 (m, 2H), 1.97-1.87 (m,2H), 1.59-1.47 (m, 2H), 1.15 (d, J=6.1 Hz, 6H), 1.02 (t, J=7.3 Hz, 3H).

EXAMPLE 75 Compound of Formula I2-Butyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-4-amine

[0366]

[0367] Under a nitrogen atmosphere, trichloroacetyl isocyanate (0.42 mL,3.5 mmol) was added dropwise to a solution of2-butyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide(0.8 g, 2.3 mmol) in dichloromethane (25 mL). The reaction mixture wasmaintained at ambient temperature for 2 hours and then concentratedunder vacuum to provide a yellow oil. The oil was dissolved in methanol(15 mL) and then sodium methoxide (0.8 mL of 25% in methanol, 3.5 mmol)was slowly added. The reaction was maintained at ambient temperatureovernight. The resulting precipitate was isolated by filtration and thenrecrystallized from methyl acetate to provide 0.47 g of 2-butyl-1(3-isopropoxypropyl)-1H-imidazo[4,5-c][1,5]naphthyridine-4-amine as awhite crystalline solid, m.p. 174-175° C. Analysis: Calculated forC₁₉H₂₇N₅O: % C, 66.83; % H, 7.97; % N, 20.51; Found: % C, 66.70; % H,7.81; % N, 20.75. ¹H NMR (300 MHz, CDCl₃): δ 8.50 (dd, J=4.3, 1.5 Hz,1H), 7.90 (dd, J=8.4, 1.5 Hz, 1H), 7.42 (dd, J=8.4, 4.3 Hz, 1H), 6.75(s, 2H), 4.77 (t, J=6.8 Hz, 2H), 3.50 (pentet, J=6.1 Hz, 1H), 3.35 (m,2H), 2.95 (t, J=7.8 Hz, 2H), 2.13-2.04 (m, 2H), 1.86-1.76 (m, 2H),1.52-1.40 (m, 2H), 1.05 (d, J=6.1 Hz, 6H), 0.97 (t, J=7.3 Hz, 3H).

EXAMPLE 76 Compound of Formula XXXIN⁴-(3-Butoxypropyl)-3-nitro[1,5]naphthyridin-4-amine

[0368] Under a nitrogen atmosphere, 3-butoxypropylamine (4.0 mL, 26mmol) was added dropwise over a period of 10 minutes to a solution of4-chloro-3-nitro[1,5]naphthyridine (4.6 g, 22 mmol) and triethylamine(4.6 mL, 33 mmol) in dichloromethane (150 mL). The reaction mixture wasmaintained at ambient temperature overnight. Water (100 mL) was addedand the phases were separated. The aqueous phase was extracted withdichloromethane (100 mL). The organic fractions were combined, driedover magnesium sulfate, filtered and then concentrated under vacuum toprovide a yellow oil. The oil was purified by flash chromatography(silica gel eluting with 1:1 ethyl acetate:hexanes) to provide 5.3 g ofN⁴-(3-butoxypropyl)-3-nitro[1,5]naphthyridin-4-amine as a colorless oil.¹H NMR (300 MHz, CDCl₃): δ 10.08 (broad s, 1H), 9.38 (broad s, 1H), 8.78(m, 1H), 8.22 (dd, J=8.4, 1.6 Hz, 1H), 7.64 (dd, J=8.4, 4.1 Hz, 1H),4.57 (broad s, 2H), 3.63 (t, J=5.8 Hz, 2H), 3.46 (t, J=6.7 Hz, 2H),2.10-2.03 (m, 2H), 1.65-1.55 (m, 2H), 1.44-1.32 (m, 2H), 0.92 (t, J=7.3Hz, 3H); MS (ED: m/e 304.1535 (304.1535 calc'd for C₁₅H₂₀N₄O₃).

EXAMPLE 77 Compound of Formula XXXIIN⁴-(3-Butoxypropyl)[1,5]naphthyridine-3,4-diamine

[0369] Using the method of Example 72,N⁴-(3-butoxypropyl)-3-nitro[1,5]naphthyridin-4-amine (4.9 g, 16 mmol)was reduced to provide 4.3 g ofN⁴-(3-butoxypropyl)[1,5]naphthyridine-3,4-diamine as a bright yellowoil. Analysis: Calculated for C₁₅H₂₂N₄O: % C, 65.67; % H, 8.08; % N,20.42; Found: % C, 65.48; % H, 8.07; % N, 20.41. ¹H NMR (300 MHz,CDCl₃): :88.70 (dd, J=4.1, 1.6 Hz, 1H), 8.39 (s, 1H), 8.18 (dd, J=8.4,1.6 Hz, 1H), 7.37 (dd, J=8.4, 4.1 Hz, 1H), 5.97 (broad s, 1H), 3.96(broad s, 2H), 3.63-3.56 (m, 4H), 3.44 (t, J=6.7 Hz, 2H), 1.89 (pentet,J=6.2 Hz, 2H), 1.63-1.53 (m, 2H), 1.44-1.32 (m, 2H), 0.93 (t, J=7.3 Hz,3H); MS (EI): m/e 274.1799 (274.1793 calc'd for C₁₅H₂₂N₄O).

EXAMPLE 78 Compound of Formula XXXIII1-(3-Butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine

[0370] Using the general method of Example 73 Part A and Part B,N⁴-(3-butoxypropyl)[1,5]naphthyridine-3,4-diamine (3.7 g, 13.5 mmol) wasreacted with valeryl chloride (1.7 mL, 14.3 mmol) and the resultingamide intermediate was cyclized to provide 2.9 g of1-(3-butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine as acolorless oil. A small portion was purified by flash chromatography(silica gel eluting with ethyl acetate) to provide a pure sample as awhite powder, m.p. 56.5-57.5° C. Analysis: Calculated for C₂₀H₂₈N₄O: %C, 70.56; % H, 8.29; % N, 16.46; Found: % C, 70.48; % H, 8.25; % N,16.61. ¹H NMR (300 MHz, CDCl₃): δ 9.32 (s, 1H), 8.90 (dd, J=4.3, 1.6 Hz,1H), 8.49 (dd, J=8.5, 1.6 Hz, 1H), 7.57 (dd, J=8.5, 4.3 Hz, 1H), 4.94(t, J=7.0 Hz, 2H), 3.45-3.39 (m, 4H), 3.04 (t, J=7.9 Hz, 2H), 2.26(pentet, J=6.1 Hz, 2H), 2.01-1.91 (m, 2H), 1.62-1.48 (m, 4H), 1.45-1.33(m, 2H), 1.03 (t, J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H).

EXAMPLE 79 Compound of Formula XXXIV1-(3-Butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

[0371] Using the general method of Example 74,1-(3-butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine (2.2 g,6.47 mmol) was oxidized to provide 1.6 g of1-(3-butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxideas a yellow powder, m.p. 126.5-127.5° C. Analysis: Calculated forC₂₀H₂₈N₄O₂: % C, 67.39; % H, 7.92; % N, 15.72; Found: % C, 67.13; % H,7.69; % N, 15.82. ¹H NMR (300 MHz. CDCl₃): δ 9.22 (dd, J=8.8, 1.5 Hz,1H), 9.04 (s, 1H), 8.99 (dd, J=4.3, 1.5 Hz, 1H), 7.65 (dd, J=8.8, 4.3Hz, 1H), 4.89 (t, J=7.0 Hz, 2H), 3.46-3.39 (m, 4H), 3.01 (t, J=7.9 Hz,2H), 2.28-2.20 (m, 2H), 1.97-1.87 (m, 2H), 1.62-1.46 (m, 4H), 1.45-1.33(m, 2H), 1.03 (t, J=7.3 Hz, 3H), 0.94 (t, J=7.3 Hz, 3H).

EXAMPLE 80 Compound of Formula I1-(3-Butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine

[0372]

[0373] Using the general method of Example 75,1-(3-butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide(1.2 g, 3.4 mmol) was reacted with trichloroacetyl isocyanate (0.6 mL,5.0 mmol) and the resulting intermediate was hydrolyzed to provide 0.86g of1-(3-butoxypropyl)-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine asa white powder, m.p. 101.0-101.5° C. Analysis: Calculated for C₂₀H₂₉N₅O:% C, 67.58; % H, 8.22; % N, 19.70; Found: % C, 67.55; % H, 7.96; % N,20.10. ¹H NMR (300 MHz, DMSO): δ 8.50 (dd, J=4.4, 1.5 Hz, 1H), 7.91 (dd,J=8.4, 1.6 Hz, 1H), 7.42 (dd, J=8.4, 4.4 Hz, 1H), 6.77 (s, 2H), 4.78 (t,J=6.9 Hz, 2H), 3.38-3.30 (m, 4H), 2.93 (t, J=7.8 Hz, 2H), 2.11 (pentet,J=6.1 Hz, 2H), 1.82 (pentet, J=7.6 Hz, 2H), 1.51-1.39 (m, 4H), 1.37-1.25(m, 2H), 0.96 (t, J=7.3 Hz, 3H), 0.88 (t, J=7.2 Hz, 3H).

EXAMPLE 81 Compound of Formula XXXIN⁴-(2-Phenoxyethyl)-3-nitro[1,5]naphthyridin-4-amine

[0374] Using the general method of Example 76,4-chloro-3-nitro[1,5]naphthyridine (5.0 g, 24 mmol) was reacted with2-phenoxyethylamine (3.5 mL, 27 mmol) to provide 6.6 g ofN⁴-(2-phenoxyethyl)-3-nitro[1,5]naphthyridin-4-amine as a yellow solid,m.p. 107-108° C. Analysis: Calculated for C₁₆H₁₄N₄O₃: % C, 61.93; % H,4.55; % N, 18.05; Found: % C, 61.99; % H, 4.58; % N, 18.42. ¹H NMR (300MHz, DMSO): δ 10.25 (broad s, 1H), 9.39 (broad s, 1H), 8.81 (dd, J=4.1,1.7 Hz, 1H), 8.25 (dd, J=8.5, 1.7 Hz, 1H), 7.67 (dd, J=8.5, 4.1 Hz, 1H),7.34-7.26 (m, 2H), 7.01-6.96 (m, 3H), 4.89 (broad s, 2H), 4.35 (t, J=5.1Hz, 2H); MS (EI: m/e 310.1065 (310.1065 calc'd for C₁₆H₁₄N₄O₃).

EXAMPLE 82 Compound of Formula XXXIIN⁴-(2-Phenoxyethyl)[1,5]naphthyridine-3,4-diamine

[0375] Using the general method of Example 77,N⁴-(2-phenoxyethyl)-3-nitro[1,5]naphthyridin-4-amine (5.4 g, 17.4 mmol)was reduced to provide 4.6 g ofN⁴-(2-phenoxyethyl)[1,5]naphthyridine-3,4-diamine as a bright yellowoil. ¹H NMR (300 MHz. DMSO): δ 8.68 (dd, J=4.1, 1.7 Hz, 1H), 8.40 (s,1H), 8.10 (dd, J=8.4, 1.7 Hz, 1H), 7.39 (dd, J=8.4, 4.1 Hz, 1H),7.28-7.22 (m, 2H), 6.94-6.90 (m, 3H), 6.12 (t, J=7.0 Hz, 1H), 5.15 (s,2H), 4.13 (t, J=5.5 Hz, 2H), 3.93-3.87 (m, 2H); MS (CI): m/e 281 (M+H).

EXAMPLE 83 Compound of Formula XXXIII2-(2-Butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl Phenyl Ether

[0376] Using the general method of Example 73 Part A and Part B,N⁴-(2-phenoxyethyl)[1,5]naphthyridine-3,4-diamine (4.4 g, 15.7 mmol) wasreacted with valeryl chloride (1.95 mL, 16.4 mmol) and the resultingamide intermediate was cyclized to provide 4.0 g of2-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl phenyl ether asa white solid, m.p. 150-150.5° C. Analysis: Calculated for C₂₁H₂₂N₄O: %C, 72.81; % H, 6.40; % N, 16.17; Found: % C, 72.78; % H, 6.40; % N,16.31. ¹H NMR (300 MHz, DMSO): δ 9.25 (s, 1H), 9.00 (dd, J=4.3,1.7 Hz,1H), 8.52 (dd, J=8.4, 1.7 Hz, 1H), 7.74 (dd, J=8.4, 4.3 Hz, 1H),7.25-7.20 (m, 2H), 6.91-6.84 (m, 3H), 5.22 (t, J=5.2 Hz, 2H), 4.53 (t,J=5.2 Hz, 2H), 3.09 (t, J=7.7 Hz, 2H), 1.91 (pentet, J=7.6 Hz, 2H),1.55-1.43 (m, 2H), 0.97 (t, J=7.3 Hz, 3H); MS I): m/e 346.1794 (346.1793calc'd for C₂₁H₂₂N₄O).

EXAMPLE 84 Compound of Formula XXXIV2-Butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

[0377] Using the general method of Example 74,2-(2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl phenyl ether(0.6 g, 1.7 mmol) was oxidized to provide 0.44 g of2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxideas a yellow powder. ¹H NMR (300 MHz, CDCl₃): δ 9.10-9.03 (m, 3H), 7.81(dd, J=8.7, 4.3 Hz, 1H), 7.25-7.20 (m, 2H), 6.92-6.83 (m, 3H), 5.16 (t,J=4.9 Hz, 2H), 4.51 (t, J=4.9 Hz, 2H), 3.06 (t, J=7.7 Hz, 2H), 1.93-1.83(m, 2H), 1.54-1.41 (m, 2H), 0.96 (t, J=7.3 Hz, 3H); MS (CI): m/e 363(M+H).

EXAMPLE 85 Compound of Formula I2-Butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine

[0378]

[0379] Using the general method of Example 75,2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide(0.38 g, 1.05 mmol) was reacted with trichloroacetyl isocyanate (0.19mL, 1.6 mmol) and the resulting intermediate was hydrolyzed to provide0.23 g of2-butyl-1-(2-phenoxyethyl)-1H-imidazo[4,5-c][1,5]naphthyridin-4-amine asa white powder, m.p. 159.0-159.2° C. ¹H NMR (300 MHz. DMSO): δ 8.52 (dd,J=4.4, 1.5 Hz, 1H), 7.92 (dd, J=8.4, 1.5 Hz, 1H), 7.45 (dd, J=8.4, 4.4Hz, 1H), 7.26-7.21 (m, 2H), 6.92-6.86 (m, 3H), 6.79 (s, 2H) 5.13 (t,J=5.2 Hz, 2H), 4.48 (t, J=5.2 Hz, 2H), 3.00 (t, J=7.8 Hz, 2H), 1.91-1.81(pentet, J=7.4 Hz, 2H), 1.52-1.40 (m, 2H), 0.95 (t, J=7.3 Hz, 3H); MS(EI): me 361.1899 (361.1902 calc'd for C₂₁H₂₃N₅O).

EXAMPLE 86 Compound of Formula XXXI 1,1-DimethylethylN-{2-[(3-Nitro[1,5]naphthyridin-4-yl)amino]ethyl}carbamate

[0380] A solution of diisopropylethylamine (13.47 g, 0.10 mole) indichloromethane (25 mL) was added to a solution of5-chloro-3-nitro[1,5]naphthyridine (18.2 g, 0.086 mol) indichloromethane (250 mL). A solution of tert-butylN-(2-aminoethyl)carbamate (16.7 g, 0.10 mol) in dichloromethane (75 mL)was slowly added to the reaction mixture. The reaction mixture washeated at reflux overnight. Additional tert-butylN-(2-aminoethyl)carbamate (1 g) was added and the reaction mixture washeated at reflux for an additional 3 hours. The reaction mixture wasallowed to cool to ambient temperature and then it was diluted withadditional dichloromethane, washed with water and with brine, dried, andthen concentrated under vacuum to provide a dark solid. This solid waspurified by flash chromatography (silica gel eluting withdichloromethane) to provide 24.8 g of 1,1-dimethylethylN-{2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethylcarbamate as a canaryyellow solid. A portion (0.3 g) was recrystallized from toluene (10 mL)and heptane (10 mL) to provide 0.2 g of canary yellow needles, m.p.149-151° C. Analysis: Calculated for C₁₅H₁₉N₅O₄: % C, 54.05; % H, 5.75;% N, 21.01; Found: % C, 54.17; % H, 5.73; % N, 20.90.

EXAMPLE 87 Compound of Formula XXXII 1,1-DimethylethylN-{2-[(3-Amino[1,5]naphthyridin-4-yl)amino]ethyl}carbamate

[0381] 1,1-DimethylethylN-{2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethyl}carbamate (10 g, 0.03mol), ethyl acetate (800 mL) and platinum on carbon catalyst werecombined in a Parr bottle and then the mixture was hydrogenatedovernight. The reaction mixture was filtered to remove the catalyst. Thefiltrate was concentrated under vacuum to provide 9.1 g of1,1-dimethylethylN-{2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethyl}carbamate as a yellowsyrup. Analysis: Calculated for C₁₅H₂₁N₅O₂+0.1 CH₃CO₂C₂H₅: % C, 59.25; %H, 7.04; % N, 22.43; Found: % C, 58.96; % H, 6.87; % N, 22.46.

EXAMPLE 88 Compound of Formula XXXIII 1,1-DimethylethylN-[2-(B-butyl-1H-imidazo[4,5-c]1,5]naphthyridin-1-yl)ethyl]carbamate

[0382] 1,1-DimethylethylN-{2-[(3-amino[1,5]naphthyridin-4-yl)amino]ethyl}carbamate 0.6 g, 2mmol), trimethyl orthovalerate (0.35 g, 2.1 mmol), and toluene (25 mL)were combined and heated at reflux for 2 hours. Additional trimethylorthovalerate (1 eq.) was added and the reaction mixture was heated atreflux overnight. Xylene was added and the toluene was distilled off.The reaction was heated at reflux for an additional 8 hours. The bulk ofthe xylene was distilled off leaving a volume of about 5 mL. Thereaction mixture was allowed to cool. The resulting precipitate wasisolated by filtration, washed with heptane and dried to provide 0.35 gof 1,1-dimethylethylN-[2-(2-butyl-1H-imidazo[4,5-c]1,5]naphthyridin-1-yl)ethyl]carbamate asan ivory powder, m.p. 198-199° C. Analysis: Calculated for C₂₀H₂₇N₅O₂: %C, 65.01; % H, 7.36; % N, 18.95; Found: % C, 64.75; % N, 7.57; % N,19.09.

EXAMPLE 89 Compound of Formula XXXIII1-{2-[(1,1-dimethylethoxycarbonyl)amino]ethyl}-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide

[0383] 3-Chloroperbenzoic acid (0.7 g of 57-86%) was dissolved inchloroform (10 mL). One half of this solution was added to a solution of1,1-dimethylethylN-[2-(2-butyl-1H-imidazo[4,5-c]1,5]naphthyridin-1-yl)ethyl]carbamate(1.0 g, 2.7 mmol) in chloroform (10 mL). The reaction mixture wasstirred at ambient temperature for 30 minutes and then the remaininghalf of the chloroperbenzoic acid solution was added dropwise to thereaction mixture. The reaction mixture was stirred at ambienttemperature for a total of 2.5 hours and then it was diluted withchloroform (50 mL); washed with sodium carbonate, with 10% sodiumhydroxide, with water, and with brine; dried and concentrated undervacuum to provide 1.1 g of a yellow solid. This material wasrecrystallized twice from acetonitrile to provide 1.0 g of1-{2-[(1,1-dimethylethoxycarbonyl)amino]ethyl}-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide.Analysis: Calculated for C₂₀H₂₇N₅O₃: % C, 62.32; % H, 7.06; % N, 18.17;Found: % C, 62.03; % H, 6.73; % N, 18.10.

EXAMPLE 90 Compound of Formula I 1,1-DimethylethylN-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]carbamate

[0384]

[0385] Trichloroacetyl isocyanate (4.8 mL, 40 mmol) was added via asyringe to a solution of1-{2-[(1,1-dimethylethoxycarbonyl)amino]ethyl}-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide(10.4 g, 27 mmol) in dichloromethane (75 mL). The reaction mixture wasstirred at ambient temperature for 1 hour. Sodium methoxide (9 mL of 25%sodium methoxide in methanol) was added and the reaction mixture wasstirred at ambient temperature overnight. Thin layer chromatographyindicated that the reaction was not complete so additional sodiummethoxide was added twice with each addition being followed by 2 hoursof stirring at ambient temperature. The reaction mixture was dilutedwith dichloromethane; washed with sodium carbonate, water, and thenbrine; dried and then concentrated under vacuum to provide 10.4 g of ayellow solid. This material was purified by column chromatography(silica gel eluting with dichloromethane) to provide 8.5 g of a solid.This solid was recrystallized from toluene (20 mL) to provide 6.0 g of1,1-dimethylethylN-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]carbamateas ivory crystals, m.p. 118-120° C. Analysis: Calculated for C₂₀H₂₈N₆O₂:% C, 62.48; % H, 7.34; % N, 21.85; Found: % C, 62.31; % H, 7.23; % N,22.13. HRMS (EI) calcd for C₂₀H₂₈N₆O₂ (M⁺) 384.2273, found 384.2273

EXAMPLE 91 Compound of Formula I2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine

[0386]

[0387] Trifluoroacetic acid (5 mL) was added to a solution of1,1-dimethylethylN-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]carbamate(5.7 g, 15 mmol) in dichloromethane (10 mL). The reaction mixture wasstirred at ambient temperature for 1 hour. The reaction mixture wasdiluted with dichloromethane and then extracted with 10% hydrochloricacid. The hydrochloric acid extract was washed twice withdichloromethane and then it was made basic with ammonium hydroxide. Theresulting precipitate was isolated by filtration and dried to provide3.7 g of2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamineas a white powder, m.p. 175-176° C. Analysis: Calculated for C₁₅H₂₀N₆: %C, 63.36; % H, 7.09; % N, 29.55; Found: % C, 62.98; % H, 6.92; % N,29.89. HRMS (EI) calcd for C₁₅H₂₀N₆ (M⁺) 284.1749, found 284.1748.

EXAMPLE 92 Compound of Formula IN¹-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]acetamide

[0388]

[0389] Under a nitrogen atmosphere, acetyl chloride (50 μL, 0.7 mmole)in dichloromethane (25 mL) was added dropwise to a cooled (ice bath)solution of2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.2 g, 0.7 mmol) in dichloromethane (50 mL). After the addition wascomplete, the reaction mixture was allowed to warm to ambienttemperature. After 30 minutes thin layer chromatography indicated thatthe reaction was complete. The reaction mixture was washed with 10%sodium hydroxide, water and brine; dried; and concentrated under vacuumto provide 0.25 g of crude product. This material was purified by columnchromatography (silica gel eluting with dichloromethane) to provide 0.2g of a solid. This solid was recrystallized from acetonitrile (30 mL) toprovide 0.18 g ofN′-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]acetamideas a white powder, m.p. 228-230° C. Analysis: Calculated for C₁₇H₂₂N₆O:% C, 62.56; % H, 6.79; % N, 25.75; Found: % C, 62.50; % H, 6.59; % N,26.04. HRMS (EI) calcd for C₂₂H₂₆N₆O₂ (M⁺) 326.1855, found 326.1846

EXAMPLE 93 Compound of Formula IN¹-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-(E)-2-butenamide

[0390]

[0391] Using the general method of Example 92, crotonyl chloride (68 μL,0.7 mmol) was reacted with2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.2 g, 0.7 mmol) to provide 0.2 g ofN-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-(E)-2-butenamideas a white powder, m.p. 198-200° C. Analysis: Calculated for C₁₉H₂₄N₆O:% C, 64.75; % H, 6.86; % N, 23.85; Found: % C, 64.25; % H, 6.68; % N,23.99. HRMS (EI) calcd for C₁₉H₂₄N₆O (M⁺) 352.2011 found 352.1996

Example 94 Compound of Formula IN¹-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-1-cyclohexanecarboxamide

[0392]

[0393] Using the general method of Example 92, cyclohexanecarbonylchloride (94 μL, 0.7 mmol) was reacted with2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.2 g, 0.7 mmol) to provide 0.2 g ofN-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-1-cyclohexanecarboxamideas a white powder, m.p. 188-190° C. Analysis: Calculated for C₂₂H₃₀N₆O:% C, 66.98; % H, 7.66; % N, 21.30; Found: % C, 66.72; % H, 7.57; % N,21.48. HRMS (ED calcd for C₂₂H₃₀N₆O (M⁺) 394.2481 found 394.2475.

EXAMPLE 95 Compound of Formula IN′-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-di-(1,1-dimethylethyl)-4-hydroxybenzamide

[0394]

[0395] Using the general method of Example 92,3,5-di-(1,1dimethylethyl)-4-hydroxybenzoyl chloride (0.47 g, 1.7 mmol)was reacted with2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.5 g, 1.7 mmol) to provide 0.5 g ofN¹-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-di-(1,1-dimethylethyl)-4-hydroxybenzamideas a white powder, m.p. 248-250° C. Analysis: Calculated for C₃₀H₄₀N₆O₂:% C, 69.74; % H, 7.80; % N, 16.27; Found: % C, 69.65% H, 7.69; % N,16.42. HRMS (EI) calcd for C₃₀H₄₀N₆O₂ (M⁺) 516.3212 found 516.3226

EXAMPLE 96 Compound of Formula IN¹-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3-phenylpropanamideHydrochloride

[0396]

[0397] Using the general method of Example 92, hydrocinnamoyl chloride(0.1 g, 0.7 mmol) was reacted with2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.2 g, 0.7 mmol). After one hour the reaction mixture was poureddirectly onto a silica gel column and eluted with dichloromethane atfirst, then 15% methanol/dichloromethane to provide 0.2 g of a solid.This solid was recrystallized from toluene to provide 0.2 g ofN¹-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3-phenylpropanamidehydrochloride as a white powder, m.p. 183-185° C. Analysis: Calculatedfor C₂₄H₂₈N₆OHCl: % C, 63.64; % H, 6.45; % N, 18.55; Found: % C, 63.68;% H, 6.43; % N, 18.55.

EXAMPLE 97 Compound of Formula IN-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-5-oxotetrahydro-2-furancarboxamide

[0398]

[0399] A solution of (S)-(+)-5-oxo-2-tetrahydrofurancarboxylic acid(0.23 g, 1.7 mmole in anhydrous dichloromethane (30 mL) was slowly addedto a solution of2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.5 g, 1.7 mmol) in anhydrous dichloromethane (100 mL). The reactionmixture was stirred at ambient temperature for 30 minutes and then asolution of 1-[3-(dimethoxyamino)propyl]-3-ethylcarbodiimidehydrochloride (0.37 g, 1.9 mmol) in anhydrous dichloromethane (50 mL)was added dropwise. The reaction mixture was stirred at ambienttemperature overnight and then filtered to remove solids. The filtratewas washed twice with 10% sodium hydroxide and then with brine, dried,and then concentrated under vacuum to provide 0.3 g of crude product.This material was purified by column chromatography (silica gel elutingwith dichloromethane) followed by recrystallization from acetonitrile toprovide 0.1 g ofN-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-5-oxotetrahydro-2-furancarboxamideas a white powder, m.p. 153-154° C. Analysis: Calculated for C₂₀H₂₄N₆O₃:% C, 60.59; % H, 6.10; % N, 21.19; Found: % C, 60.34; % H, 6.14; % N,21.13. HRMS (EI) calcd for C₂₀H₂₄N₆O₃ (M⁺) 396.1909 found 396.1905

EXAMPLE 98 Compound of Formula IN′-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-2-(3-hydroxyphenyl)acetamide

[0400]

[0401] Using the general method of Example 97 3-hydroxyphenyl aceticacid (0.26 g, 1.7 mmole) was reacted with2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.5 g, 1.7 mmol) to provide 0.13 g ofN¹-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-2-(3-hydroxyphenyl)acetamideas a white powder, m.p. 208-210° C. Analysis: Calculated for C₂₃H₂₆N₆O₂:% C, 66.01; % H, 6.26; % N, 20.08; Found: % C, 65.63; % H, 6.11; % N,20.30. HRMS (ED) calcd for C₂₃H₂₆N₆O₂ (M⁺) 418.2117 found 418.2109.

Example 99 Compound of Formula IN-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-6-hydroxy-2-pyridinecarboxamide

[0402]

[0403] Using the general method of Example 976-hydroxypicolinic acid(0.24 g, 1.7 mmole) was reacted with2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.5 g, 1.7 mmol) to provide 0.15 g ofN-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-6-hydroxy-2-pyridinecarboxamideas a white powder, m.p. 258-260° C. Analysis: Calculated forC₂₁H₂₃N₇O₂+½CH₃CN: % C, 62.03; % H, 5.80; % N, 24.66; Found: % C, 61.87;% H, 5.70; % N, 24.60.

Example 100 Compound of Formula IN′-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,7-dimethyl-6-octenamide

[0404]

[0405] Using the general method of Example 97 citronellic acid (0.3 g,1.7 mmole) was reacted with2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.5 g, 1.7 mmol) to provide 0.5 g ofN¹-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,7-dimethyl-6-octenamideas a white whispy solid, m.p. 163-164° C. Analysis: Calculated forC₂₅H₃₆N₆O: % C, 68.77; % H, 8.31; % N, 19.25; Found: % C, 68.84; % H,8.14; % N, 19.58. HRMS (EI) calcd for C₂₅H₃₆N₆O (M⁺) 436.2950 found436.2952.

EXAMPLE 101 Compound of Formula I 1,1-DimethylethylN-[1-({[2-(4-Amino-2-butyl-1-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]amino}carbonyl)-3-methylbutyl]carbamate

[0406]

[0407] Using the general method of Example 97N-t-BOC-L-leucine (0.41 g,1.7 mmole) was reacted with2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.5 g, 1.7 mmol) to provide 0.5 g of 1,1-dimethylethylN-[1-({[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]amino}carbonyl)-3-methylbutyl]carbamateas a white solid, m.p. 184-185° C. HRMS (EI) calcd for C₂₆H₃₉N₇O₃ (M⁺)497.3114 found 497.3093.

EXAMPLE 102 Compound of Formula IN¹-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-2-amino-4-methylpentanamide

[0408]

[0409] 1,1-DimethylethylN-[1-({[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]amino}carbonyl)-3-methylbutyl]carbamate(0.35 g, 0.7 mmol) was combined with 1 N hydrochloric acid (40 mL) andheated on a steam bath for 30 minutes. The reaction mixture was allowedto cool and then it was made basic with 10% sodium hydroxide. Theresulting precipitate was isolated by filtration and dried to provide0.15 g ofN¹-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-2-amino-4-methylpentamideas a white solid, m.p. 60-65° C. Analysis: Calculated for C₂₁H₃₁N₇O: %C, 63.27; % H, 7.86; % N, 24.66; Found: % C, 62.27; % H, 7.67; % N,24.77. HRMS (EI) calcd for C₂₁H₃₁N₇O (M⁺) 397.2590 found 397.2582.

EXAMPLE 103 Compound of Formula IN-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-dimethyl-4-isoxazolecarboxamide

[0410]

[0411] Using the general method of Example973,5-dimethylisoxazole-4-carboxylic acid (0.25 g, 1.7 mmole) wasreacted with2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.5 g, 1.7 mmol) to provide 0.23 g ofN-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-dimethyl-4-isoxazolecarboxamideas a white powder, m.p. 188-189° C. Analysis: Calculated for C₂₁H₂₅N₇O₂:% C, 61.90; % H, 6.18; % N, 24.06; Found: % C, 61.92; % H, 6.15; % N,24.28. HRMS (EI) calcd for C₂₁H₂₅N₇O₂ (M⁺) 407.2069 found 407.2068

EXAMPLE 104 Compound of Formula IIN¹-[2-(4-Amino-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c][195]naphthyridin-1-yl)ethyl]-3,5-di-(1,1-dimethylethyl)₄-hydroxybenzamide

[0412]

[0413] A solution ofN¹-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-di-(1,1-dimethylethyl)-4-hydroxybenzamide(0.1 g, 0.19 mmol) in trifluoroacetic acid (15 mL) and platinum oxide(0.1 g) were combined and hydrogenated overnight on a Parr apparatus.The reaction mixture was filtered to remove the catalyst. The filtratewas concentrated under vacuum. The residue was dissolved indichloromethane. The dichloromethane solution was washed twice with 10%sodium hydroxide and with brine, dried and then concentrated undervacuum to provide crude product. This material was purified bychromatography eluting with 10% methanol in dichloromethane. Theresulting oil was triturated with acetonitrile to provide 0.05 g ofN¹-[2-(4-amino-2-butyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-3,5-di-(11,1-dimethylethyl)-4-hydroxybenzamideas a white powder, m.p. 208-210° C. Analysis: Calculated forC₃₀H₄₄N₆O₂+0.1CF₃CO₂H: % C, 68.17; % H, 8.35; ON, 15.79; Found: % C,68.48; % H, 8.29; % N, 16.08.

EXAMPLE 105 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-5-(1,3-dimethyl-2,6-oxo-2,3,6,7-tetrahydro-1H-purinyl)pentamide

[0414]

[0415]4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.2 g), 5-(1,3-dimethyl-2,6-oxo-2,3,6,7-tetrahydro-1H-purinyl)pentanoicacid (0.18 g) and dichloromethane (100 mL) were combined and stirred atambient temperature for 30 minutes.1-[3-(Dimethylamino)propy]-3-ethylcarbodiimide (0.12 g) was added andthe reaction mixture was stirred at ambient temperature for 2 hours. Thereaction was filtered through a column of silica gel and eluted with 10%methanol in dichloromethane to provide 0.2 g ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-5-(1,3-dimethyl-2,6-oxo-2,3,6,7-tetrahydro-1H-purinyl)pentamide,m.p. 153.5-155° C. Analysis: Calculated for C₂₉H₃₈N₁₀O₃: % C, 60.61; %H, 6.66; % N, 24.37; Found: % C, 60.65; % H, 6.66; % N, 24.32.

EXAMPLE 106 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-6-morpholinonicotinamide

[0416]

[0417] Using the general method of Example 105 6-morpholinonicotinicacid (0.12 g, 64 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.2 g, 0.64 mmol) to provideN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-6-morpholinonicotinamideas a white solid, m.p. 95-100° C. Calculated for C₂₇H₃₄N₈O₂+½H₂O: % C,63.39; % H, 6.90: % N, 21.90; Found: % C, 63.69; % H, 6.95; % N, 21.52.

EXAMPLE 107 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-6-quinolinecarboxamide

[0418]

[0419] Using the general method of Example 105 6-quinolinecarboxylicacid (0.11 g, 64 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.2 g, 0.64 mmol) to provideN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-6-quinolinecarboxamideas a white solid, m.p. 190-191° C. Analysis: Calculated forC₂₇H₂₉N₇O+¼H₂O: % C, 68.70; % H, 6.30; % N, 20.77; Found: % C, 68.54; %H, 6.21; % N, 20.93.

EXAMPLE 108 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(4-hydroxy-5-methyl-2-oxo-1,2-dihydro-1-pyrimidinyl)acetamide

[0420]

[0421] Using the general method of Example 1052-(4-hydroxy-5-methyl-2-oxo-1,2-dihydro-1-pyrimidinyl)acetic acid (0.12g, 64 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.2 g, 0.64 mmol) to provide 0.06 g ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(4-hydroxy-5-methyl-2-oxo-1,2-dihydro-1-pyrimidinyl)acetamideas a solid, m.p. 242-244° C.

EXAMPLE 109 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(2-pyrimidinylsulfanyl)acetamide

[0422]

[0423] Using the general method of Example 105 (2-pyrimidinylthio)aceticacid (0.11 g, 64 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.2 g, 0.64 mmol) to provideN′-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(2-pyrimidinylsulfanyl)acetamideas a white solid, m.p. 156-160° C. (dec.).

EXAMPLE 110 Compound of Formula IN′-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(4-pyridylsulfanyl)acetamide

[0424]

[0425] Using the general method of Example 105 (4-pyridylthio)aceticacid (0.11 g, 64 mmol) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.2 g, 0.64 mmol) to provide 0.1 g ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-2-(4-pyridylsulfanyl)acetamideas a solid, m.p. 127.5-129° C.

EXAMPLE 111 Compound of Formula I4-(4-amino-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine

[0426]

[0427] Part A

[0428] Triethylorthoformate (2.8 mL, 16.6 mmol) was added to a solutionof 1,1-dimethylethylN-{4-[(3-amino[1,5]naphthyridin-4-yl)amino]butyl}carbamate (5.0 g, 15.1mmol) in toluene (150 mL). The reaction was heated at reflux overnightwith ethanol being collected in a Dean Stark trap. The reaction mixturewas heated at reflux for an additional 6 hours and thenp-toluenesulfonic acid (1.4 g, 7.5 mmol) was added and the reaction wasrefluxed overnight. A dark orange/brown oil had formed. The toluenesupernatant was decanted off and concentrated under vacuum to provide1.1 g of 1,1-dimethylethylN-[4-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate. The oilwas identified as4-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine. This materialwas reacted with 1,1-dimethylethyl-dicarbonate to provide an additional1 g of 1,1-dimethylethylN-[4-(1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate. The twolots were combined and carried on to the next step.

[0429] Part B

[0430] 3-Chloroperbenzoic acid (1.86 g of 60%) was added in smallportions to a solution of the material from Part A in chloroform (25mL). The reaction was maintained at ambient temperature overnight andthen it was diluted with 5% sodium carbonate solution. The layers wereseparated. The organic layer was concentrated under vacuum., The residuewas slurried with hot methyl acetate, cooled and then filtered toprovide 2.0 g of1-{4-[(1,1-dimethylethylcarbonyl)amino]butyl}-1H-imidazo[4,5-c][1,5]naphthyridine-5N-oxide.

[0431] Part C

[0432] Tosyl chloride (0.64 g, 3.37 mmol) was slowly added in smallportions to a solution of the material from Part B (1.2 g, 3.37 mmol) indichloromethane (20 mL). After 4 hours an additional 100 mg of tosylchloride was added to drive the reaction to completion. The reaction wasquenched with concentrated ammonium hydroxide (5 mL) and water (10 mL)and stirred at ambient temperature over the weekend. The layers wereseparated. The organic layer was concentrated under vacuum to provide atan solid. This solid was slurried in hot methyl acetate, cooled and thefiltered to provide 0.9 g of 1,1-dimethylethylN¹-[4-(4-amino-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]carbamate.

[0433] Part D

[0434] A mixture of the material from Part C and 1 N hydrochloric acid(25 mL) was heated at reflux until thin layer chromatography indicatedthat the reaction was complete. The mixture was adjusted to pH 14 with 6N sodium hydroxide. The resulting precipitate was isolated by filtrationto provide 0.2 g of4-(4-amino-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine as a paleyellow solid, m.p. 161-163° C. Mass spec (M+1)=257.09.

EXAMPLE 112 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-4-{[2-(dimethylamino)ethoxy](phenyl)methyl}benzamide

[0435]

[0436] Part A

[0437] Under a nitrogen atmosphere phenyl magnesium bromide (39 mL of 3M in ether) was added via a syringe over a period of 30 minutes to asolution of methyl 4-formylbenzoate (19.2 g, 117 mmol). The mixture wasallowed to stir for an additional 10 minutes and then it was quenched bythe addition of 1 M hydrochloric acid (125 mL). The reaction mixture wasextracted with diethyl ether (2×200 mL). The combined extracts werewashed with brine, dried over magnesium sulfate, filtered and thenconcentrated under vacuum to provide a yellow oil. This material waspurified by flash chromatography (silica gel eluting with 6:1hexanes:ethyl acetate) to provide 6.9 g of methyl 4-(

-hydroxybenzyl)benzoate as a clear oil.

[0438] Under a nitrogen atmosphere a suspension of p-toluenesulfonicacid monohydrate (10.7 g, 56 mmol) in toluene (70 mL) was heated atreflux. Water (1 mL) was collected in a Dean Stark trap. The heatingmantle was removed. To the warm mixture was added a solution of methyl4-(

-hydroxybenzyl)benzoate (3.47 g, 14 mmol) and N,N-dimethylethanolamine(2.9 mL, 28 mmol) in a minimal amount of toluene. The mixture was heatedat reflux for 20 minutes and then allowed to cool to ambienttemperature. The reaction mixture was partitioned between diethyl etherand saturated aqueous sodium bicarbonate (the aqueous layer was basic).The aqueous layer was extracted with an additional 100 mL of diethylether. The combined organic layers were dried and then concentratedunder vacuum. The residue was purified by flash chromatography (silicagel eluting with 5%, then 10% methanol in dichloromethane) to provide2.49 g of methyl 4-[

-(2-N,N-dimethylaminoethoxy)benzyl]benzoate as a colorless oil.

[0439] 1 N Sodium hydroxide (2.54 mL) was added to a solution of methyl4-[

-(2-N,N-dimethylaminoethoxy)benzyl]benzoate (0.53 g, 1.7 mmol) inmethanol (10 mL). The solution was heated at reflux for 1 hour, allowedto cool to ambient temperature and then neutralized (pH 5-6) with 1 Nhydrochloric acid (2.54 mL). The mixture was concentrated under vacuum(bath at 45° C.). The resulting residue was extracted into a mixture ofdichloromethane (15 mL) and methanol (3 mL). The extract was filteredand the filtrate was concentrated under vacuum to provide a viscousresidue. Trituration with several portions of diethyl ether provided0.39 g of 4-[

-(2-N,N-dimethylaminoethoxy)benzyl]benzoic acid as a white powder.

[0440] Part B

[0441]4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(0.130 g, 0.4175 mmol) and 4-[

-(2-N,N-dimethylaminoethoxy)benzyl]benzoic acid (0.125 g, 0.4175 mmol)were combined in dichloromethane (150 mL) and stirred at ambienttemperature until a clear solution was obtained.1-[3-(Dimethylamino)propy]-3-ethylcarbodiimide hydrochloride (0.088 g,0.46 mmol) was added and the reaction was maintained at ambienttemperature for 2 days. The volume of dichloromethane was reduced andthe concentrate was purified by flash chromatography (silica gel elutingwith 10% methanol in dichloromethane) to provide 0.085 g ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-4-{[2-(dimethylamino)ethoxy](phenyl)methyl}benzamideas a solid, m.p. 105-108° C. Mass spec (M+1)=594.30.

EXAMPLE 113 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-4-benzoylbenzamide

[0442]

[0443] Using the general method of Example 112 Part B, 4-benzoylbenzoicacid (72 mg, 0.32 mmole) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(100 mg, 0.32 mmol) to provide 30 mg ofN′-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-4-benzoylbenzamideas a white solid. Mass-spec (M+1=521.31).

EXAMPLE 114 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydro-1-pyrimidinyl)acetamide

[0444]

[0445] Using the general method of Example 112 Part B, thymine-1-aceticacid (130 mg, 0.70 mmole) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(200 mg, 0.70 mmol) to provide 68 mg ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-2-(5-methyl-2,4-dioxo-1,2,3,4-tetrahydro-1-pyrimidinyl)acetamideas a white solid, m.p. 241-242° C. Mass-spec (M+1=451.24).

EXAMPLE 115 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-6-(5-methyl-2-oxo-4-imidazolidinyl)hexamide

[0446]

[0447] Using the general method of Example 112 Part B, D-desthiobiotin(151 mg, 0.70 mmole) was reacted with4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(200 mg, 0.70 mmol) to provide 231 mg ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-6-(5-methyl-2-oxo-4-imidazolidinyl)hexamideas a white solid, m.p. 184-186° C. Mass spec (M+1=481.35).

EXAMPLE 116 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]methanesulfonamide

[0448]

[0449] Using the method of Examples below,4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(14 mg, 50 μmol) was reacted with methanesulfonyl chloride (4 μL, 50μmol) to provide 5.3 mg ofN-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]methanesulfonamide.¹H NMR (500 MHz, d6-DMSO)™=8.49 (dd, J=4.3; 1.5 Hz, 1H), 7.92 (dd,J=8.0; 1.5 Hz, 1H), 7.44 (dd, J=8.0; 4.3 Hz, 1H), 7.30 (t, J=6 Hz, 1H),6.76 (s, 2H), 4.77 (t, J=6 Hz, 2H), 3.50 (q, J=6 Hz, 2H), 2.98 (t, J=7Hz, 2H), 2.85 (s, 3H), 1.82 (quintet, J=7 Hz, 2H), 1.46 (m, 2H), 0.96(t, J=7 Hz, 3H). Mass spec by APCI (+/−) plug injection gave desired MW.

EXAMPLE 117 Compound of Formula IN¹-[4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]benzenesulfonamide

[0450]

[0451] Using the method of Examples 118-152 below,4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(14 mg, 50 μmol) was reacted with benzenesulfonyl chloride (6 μL, 50μmol) to provide 10.9 mg ofN¹-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]benzenesulfonamide.¹H NMR (500 MHz, d6-DMSO)™=8.43 (dd, J=4.4; 1.5 Hz, 1H), 7.94 (t, J=6Hz, 1H), 7.89 (dd, J=8.4; 1.5 Hz, 1H), 7.68 (d, J=8 Hz, 2H), 7.58 (t,J=8 Hz, 1H), 7.50 (t, J=8 Hz, 2H), 7.41 (dd, J=8.4; 4.4 Hz, 1H), 4.72(t, J=6 Hz, 2H), 3.34 (m, 2H), 2.97 (t, J=7 Hz, 2H), 1.81 (quintet, J=7Hz, 2H), 1.45 (sextet, J=7 Hz, 2H), 0.97 (t, J=7 Hz, 3H). Mass spec byAPCI (+/−) plug injection gave desired MW.

EXAMPLES 118-152 Compounds of Formula I

[0452] The compounds of Examples 118-152 shown in the table below wereprepared according to the following method.4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(50 μmol) was dissolved in dichloromethane (5 mL) in a screw-capped testtube and the solution was cooled in an ice-water bath. An acid chloride(50 μmol) of the formula R_(A)COCl was added as a solution in 100 μL ofdichloromethane (Acid chlorides that are solids were either dissolved orsuspended in ˜400 μL of dichloromethane and then added). The mixture wasvortexed for 15 seconds to 1 minute, becoming cloudy, and then 80 mg ofan aminomethyl polystyrene resin (0.62 meq/g, 100-200 mesh, 1%crosslink, Bachem #D-2100, lot # FM507) was added, and the mixture wasvortexed for another 30 seconds. The mixture was applied to a shortcolumn (3×1 cm) of silica gel conditioned with dichloromethane. Theproduct was eluted with 10:1 dichloromethane:methanol, collecting ˜2 mLfractions. Thin layer chromatography of the fractions was performed, andfractions with the product spot were pooled and stripped to dryness in aSavant SpeedVac. Purity was checked by reversed phase-HPLC (HPLCconditions refer to using a Hewlett Packard HP 1090 system fitted with aC18 Rainin Microsorb MV column, 4.6×50 mm, particle size=3 microns, poresize=100 Angstroms. Gradient elution: linear gradient from 100%water+0.1% trifluoroacetic acid to 100% acetonitrile+0.1%trifluoroacetic acid over 5 min. at 1 mL per minute. Detection is at 220nm and 254 nm). APCI-mass spectral data confirmed presence of theexpected molecular ion, and proton nmr data supported the expectedstructure.

Example # R_(A) Fragment ¹H NMR (500 MHz, solvent indicated) 118

(d₆-DMSO) δ 8.51 (dd, J = 4.4, 1.5 Hz, 1H), 7.91 (dd, J = 8.3, 1.5 Hz,1H), 7.46 (t, J = 6 Hz, 1H), 7.44 (dd, J = 8.3, 4.4 Hz, 1H), 6.73 (br s,2H), 4.80 (t, J = 6 Hz, 2H), 3.60 (q, J = 6 Hz, 2H), 2.87 (t, J = 7 Hz,2H), 2.0-1.8 (m, 17H), 1.43 (sextet, J = 7 Hz, 2H), 0.96 (t, J = 7 Hz,3H) 119

(d₆-DMSO) δ 8.49 (d, J = 4.5 Hz, 1H), 7.93 (d, J = 8 Hz, 1H), 7.65 (t, J= 6 Hz, 1H), 7.45 (dd, J = 4.5, 8 Hz, 1H), 7.29 (d, J = 8 Hz, 2H), 7.17(d, J = 8 Hz, 2H), 6.92 (br s, 2H), 4.69 (t, J = 6 Hz, 2H), 3.59 (q, J =6 Hz, 2H), 2.60 (t, J = 7 Hz, 2H), 2.28 (m, 2H), 1.67 (m, 4H), 1.5-1.3(m, 6H), 0.92 (t, J = 7 Hz, 3H) 120

(d₆-DMSO) δ 8.96 (t, J = 6 Hz, 1H), 8.49 (dd, J = 4.0, 1.5, 1H), 7.92(dd, J = 8, 1.5 Hz, 1H), 7.50 (d, J = 8 Hz, 2H), 7.44 (dd, J = 8, 4.0Hz, 1H), 7.40 (t, J = 8 Hz, 1H), 6.76 (s, 2H), 4.85 (t, J = 6 Hz, 2H),3.88 (q, J = 6 Hz, 2H), 3.03 (t, J = 7 Hz, 2H), 1.80 (quintet, J = 7 Hz,2H), 1.45 (sextet, J = 7 Hz, 2H), 0.96 (t, J = 7 Hz, 3H 121

(d₆-DMSO) δ 8.52 (dd, J = 4.2, 1.5 Hz, 1H), 8.04 (t, J = 6 Hz, 1H), 7.95(dd, J = 8.5, 1.5 Hz, 1H), 7.45 (dd, J = 8:5, 4.2 Hz, 1H), 7.4-7.2 (m,5H), 7.00 (br s, 2H), 4.84 (t, J = 6 Hz, 2H), 4.37 (s, 2H), 3.74 (s,2H), 3.65 (q, J = 6 Hz, 2H), 2.87 (t, J = 7 Hz, 2H), 1.77 (quintet, J =7 Hz, 2H), 1.40 (sextet, J = 7 Hz, 2H), 0.94 (t, J = 7 Hz, 3H) 122

(d₆-DMSO) δ 8.50 (dd, J = 4.4, 1.5 Hz, 1H), 7.97 (t, J = 6 Hz, 1H), 7.92(dd, J = 8.4, 1.5 Hz, 1H), 7.45 (dd, J = 8.4, 1.5 Hz, 1H), 6.75 (br s,2H), 4.762 (t, J = 6 Hz, 2H), 3.57 (s, 3H), 2.88 (t, J = 7 Hz, 2H), 2.27(t, J = 7 Hz, 4H), 2.18 (t, J = 7 Hz, 2H), 1.93 (t, J = 7 Hz, 2H), 1.80(quintet, J = 7 Hz, 2H), 2.6-1.1 (m, 12H), 0.96 (t, J = 7 Hz, 3H) 123

(d₆-DMSO) δ 8.52 (dd, J = 4.4, 1.5 Hz, 1H), 7.97 (t, J = 6 Hz, 1H), 7.95(dd, J = 8.3, 1.5 Hz, 1H), 7.45 (dd, J = 8.3, 4.4 Hz, 1H), 6.88 (br s,2H), 5.79 (m, 1H), 4.98 (d, J = 15 Hz, 1H), 4.91 (d, J = 13 Hz, 1H),4.76 (t, J = 6 Hz, 2H), 3.57 (q, J = 6 Hz, 2H), 2.88 (t, J = 7 Hz, 2H),2.00 (q, # J = 7 Hz, 2H), 1.93 (t, J = 6 Hz, 2H), 1.80 (quintet, J = 7Hz, 2H), 1.44 (sextet, J = 7 Hz, 2H), 1.5-1.1 (m, 12H), 0.96 (t, J = 6Hz, 3H) 124

(d₆-DMSO) δ 8.51 (dd, J = 4.4, 1.7 Hz, 1H), 7.96 (t, J = 6Hz, 1H), 7.92(dd, J = 8.3, 1.5 Hz, 1H), 7.44 (dd, J = 8.3, 4.4 Hz, 1H), 6.81 (br s,2H), 3.76 (t, J = 6 Hz, 2H), 3.59 (q, J = 6 Hz, 2H), 2.90 (t, J = 7 Hz,2H), 1.94 (m, 3H), 1.80 (quintet, J = 7 Hz, 2H), 1.58 (m, 2H), 1.55-1.40(m, 6H), 0.96 (m, 5H) 125

(d₆-DMSO) δ 9.32 (t, J = 6 Hz, 1H), 8.51 (dd, J = 4.4, 1.5 Hz, 1H), 8.29(br s, 1H), 8.26 (br s, 2H), 7.97 (d, J = 8 Hz, 1H), 7.44 (dd, J = 8,4.4 Hz, 1H), 7.42 (br s, 2H), 4.97 (t, J = 6 Hz, 2H), 3.88 (q, J = 6 Hz,2H), 2.86 (t, J = 7 Hz, 2H), 1.73 (quintet, J = 7 Hz, 2H), 1.30 (sextet,J = 7 Hz, 2H), 0.80 (t, J = 7 Hz, 3H) 126

(d₆-DMSO) δ 8.68 (d, J = 4.5 Hz 1H), 8.61 (t, J = 6 Hz, 1H), 8.12 (d, J= 8 Hz, 1H), 8.1 (br s, 2H), 7.62 (dd, J = 8.0, 4.5 Hz, 1H), 7.44 (dd, J= 7.5, 2 Hz, 1H), 7.41 (dt, J = 7.5, 2.0 Hz, 1H), 7.31 (dt, J = 7.5, 2.0Hz, 1H), 7.12 (dd, J = 7.5, 2 Hz, 1H), 4.91 (t, J = 6 Hz, 2H), 3.83 (q,J = 6 Hz, 2H), 3.00 (t, J = 7 Hz, 2H), 1.83 (quintet, J = 7 Hz, 2H),1.44 (sextet, # J = 7 Hz, 2H), 0.94 (t, J = 7 Hz, 3H) 127

(d₆-DMSO) δ 8.69 (t, J = 6 Hz, 1H), 8.63 (dd, J = 4, 1.5 Hz, 1H), 8.07(d, J = 8.5 Hz, 1H), 7.80 (br s, 2H), 7.65 (d, J = 2 Hz, 1H), 7.57 (dd,J = 8.5, 4.5 Hz, 1H), 7.42 (dd, J = 8, 2 Hz, 1H), 7.15 (d, J = 8 Hz,1H), 4.91 (t, J = 6 Hz, 2H), 3.82 (q, J = 6 Hz, 2H), 2.98 (t, J = 7 Hz,2H), 1.82 (quintet, J = 7 Hz, 2H), 1.44 (sextet, J = 7 Hz, 2H), 0.94 (t,J = 7 Hz, 3H) 128

(d₆-DMSO) δ 8.48 (dd, J = 4.3, 1.5 Hz, 1H), 8.25 (t, J = 6 Hz, 1H), 7.91(dd, J = 8.5, 1.5 Hz, 1H), 7.42 (dd, J = 8.5, 4.3 Hz, 1H), 7.25 (t, J =8 Hz, 1H), 6.74 (br s, 2H), 6.61 (d, J = 8 Hz, 2H), 4.80 (t, J = 6 Hz,2H), 3.76 (q, J = 6 Hz, 2H), 3.33 (s, 6H), 3.00 (t, J = 7 Hz, 2H), 1.79(quintet, J = 7 Hz, 2H), 1.44 (sextet, J = 7 Hz, 2H), 0.95 (t, J = 7 Hz,3H) 129

(d₆-DMSO) δ 8.66 (t, J = 6 Hz, 1H), 8.57 (dd, J = 4.3, 1.2 Hz, 1H), 8.00(dd, J = 8.5, 1.2 Hz, 1H), 7.69 (dd, J = 9, 5.8 Hz, 2H), 7.50 (dd, J =8.4, 4.3 Hz, 1H), 7.30 (br s, 2H), 7.25 (t, J = 9 Hz, 2H), 4.91 (t, J =6 Hz, 2H), 3.81 (q, J = 6 Hz, 2H), 2.81 (t, J = 7 Hz, 2H), 1.70(quintet, J = 7 Hz, 2H), 1.29 (sextet, J = 7 Hz, 2H), 0.81 (t, J = 7 Hz,3H) 130

(d₆-DMSO) δ 8.72 (t, J = 6 Hz, 1H), 8.52 (dd, J = 4.3, 1.5 Hz, 1H), 7.93(dd, J = 8.0, 1.5 Hz, 1H), 7.72 (d, J = 8 Hz, 2H), 7.50 (d, J = 8 Hz,2H), 7.44 (dd, J = 8, 4.3 Hz, 1H), 6.80 (br s, 2H), 4.90 (t, J = 6 Hz,2H), 3.81 (q, J = 6 Hz, 2H), 2.79 (t, J = 7 Hz, 2H), 1.70 (quintet, J =7 Hz, 2H), 1.29 (sextet, J = 7 Hz, 2H), 0.81 (t, J = 7 Hz, 3H) 131

(d₆-DMSO) δ 8.55 (dd, J = 4.3, 1.5 Hz, 1H), 8.49 (t, J = 6 Hz, 1H), 7.95(dd, J = 8.4, 1.5 Hz, 1H), 7.69 (d, J = 8 Hz, 2H), 7.46 (dd, J = 8.4,4.3 Hz, 1H), 6.93 (d, J = 8 Hz, 2H), 6.91 (br s, 2H), 4.90 (t, J = 6 Hz,2H), 3.8 (q, J ≈ 6 Hz, 2H), 3.79 (s, 3H), 2.79 (t, J = 7 Hz, 2H), 1.69(quintet, J = 7 Hz, 2H), 1.29 (sextet, J = 7 Hz, 2H), 0.80 (t, J = 7 Hz,3H) 132

(d₆-DMSO) δ 8.76 (t, J = 6 Hz, 1H), 8.53 (dd, J = 4.3, 1.5 Hz, 1H), 7.95(dd, J = 8.5, 1.5 Hz, 1H), 7.67 (br s, 1H), 7.65 (d, J = 8 Hz, 1H), 7.57(m, 1H), 7.48-7.43 (m, 2H), 7.02 (br s, 2H), 4.91 (t, J = 6 Hz, 2H),3.82 (q, J = 6 Hz, 2H), 2.81 (t, J = 7 Hz, 2H), 1.71 (quintet, J = 7 Hz,2H), 1.31 (sextet, J = 7 Hz, 2H), 0.82 (t, J = 7 Hz, 3H) 133

(d₆-DMSO) δ 8.69 (dd, J = 4.4, 1.2 Hz, 1H), 8.57 (t, J = 6 Hz, 1H), 8.22(br s, 2H). 8.12 (dd, J = 8.0, 1.2 Hz, 1H), 7.61 (m, 3H), 7.41 (d, J = 9Hz, 2H), 4.92 (t, J = 6 Hz, 2H), 3.82 (q, J = 6 Hz, 2H), 2.84 (t, J = 7Hz, 2H), 1.68 (quintet, J = 7 Hz, 2H), 1.27 (sextet, J = 7 Hz, 2H), 1.27(s, 9H), 0.78 (t, J = 7 Hz, 3H) 134

(d₆-DMSO) δ8.55 (t, J = 6 Hz, 1H), 8.54 (dd, J = 4.5, 1.5 Hz, 1H), 7.94(dd, J = 8.5, 1.5 Hz, 1H), 7.60 (d, J = 8 Hz, 2H), 7.46 (dd, J = 8.2,4.5 Hz, 1H), 7.21 (d, J = 8 Hz, 2H), 6.87 (br s, 2H), 4.90 (t, J = 6 Hz,2H), 3.80 (q, J = 6 Hz, 2H), 2.80 (t, J = 7 Hz, 2H), 2.32 (s, 3H), 1.69(quintet J = 7 Hz, 2H), 1.29 (sextet, J = 7 Hz, 2H), 0.81 (t, J = 7 Hz,3H) 135

(d₆-DMSO) δ 8.58 (dd, J = 4.4, 1.5 Hz, 1H), 8.00 (dd, J = 8.4, 1.5 Hz,1H), 7.97 (t, J = 6 Hz, 1H), 7.52 (dd, J = 8.4, 4.4 Hz, 1H), 7.35 (br s,2H), 4.77 (t, J = 6 Hz, 2H), 3.58 (q, J = 6 Hz, 2H), 2.93 (t, J = 7 Hz,2H), 1.85 (s, 2H), 1.81 (quintet, J = 7 Hz, 2H), 1.45 (sextet, J = 7 Hz,2H), 0.96 (t, J = 7 Hz, 3H), 0.87 (s, 9H) 136

(CDCl₃ at 60° C.) δ 8.56 (dd, J = 4.0, 1.5 Hz, 1H), 8.06 (dd, J = 8.5,1.5 Hz, 1H), 7.41 (dd, J = 8.8, 4.0 Hz, 1H), 6.80 (br s, 1H), 5.70 (brs, 2H), 4.94 (t, J = 6 Hz, 2H), 3.82 (q, J = 6 Hz, 2H), 2.91 (t, J = 7Hz, 2H), 1.90 (quintet, J = 7 Hz, 2H), 1.51 (sextet, J = 7 Hz, 2H), 0.99(m, 1H), 0.99 (t, J = 7 Hz, 3H), 0.79 (m, 2H), 0.54 (m, 2H) 137

(CDCl₃) δ 8.59 (dd, J = 4.5, 1.5 Hz, 1H), 8.10 (dd, J = 8.3, 1.5 Hz,1H), 7.46 (dd, J = 8.5, 4.5 Hz, 1H), 6.79 (br s, 1H), 6.02 (br s, 2H),4.96 (t, J = 6 Hz, 2H), 3.82 (q, J = 6 Hz, 2H), 2.93 (t, J = 7 Hz, 2H),2.18 (quintet, J = 7 Hz, 1H), 1.90 (quintet, J = 7 Hz, 2H), 1.65-1.35(m, 10H), 1.00 (t, J = 7 Hz, 3H) 138

(CDCl₃) δ 8.58 (dd, J = 4.4, 1.5 Hz, 1H), 8.09 (dd, J = 8.0, 1.5 Hz,1H), 7.46 (dd, J = 8.3, 4.4 Hz, 1H), 7.00 (br s, 1H), 5.85 (br s, 2H),4.96 (t, J = 6 Hz, 2H), 3.81 (q, J = 6 Hz, 2H), 2.92 (t, J = 7 Hz, 2H),1.88 (m, 3H), 1.52 (m, 6H), 1.50 (m, 2H), 1.49 (m, 2H), 1.291 (q, 2H),1.01 (t, J = 7 Hz, 3H), 0.85 (m, 2H) 139

(CDCl₃) δ 8.52 (dd, J = 4.4, 1.5 Hz, 1H), 8.26 (br t, 1H), 8.09 (dd, J =8.5, 1.5 Hz, 1H), 7.47 (d, J = 8 Hz, 2H), 7.46 (dd, J = 8.5, 4.4 Hz,1H), 7.34 (d, J = 8 Hz, 2H), 5.92 (br s, 2H), 5.12 (t, J = 6 Hz, 2H),4.04 (q, J = 6 Hz, 2H), 2.93 (t, J = 7 Hz, 2H), 1.92 (quintet, J = 7 Hz,2H), 1.52 (sextet, J = 7 Hz, 2H), 1.00 (t, J = 7 Hz, 3H) 140

(CDCl₃) δ 8.65 (dd, J = 4.4, 1.5 Hz, 1H), 8.03 (dd, J = 8.5, 1.5 Hz,1H), 7.59 (br t, 1H), 7.45 (dd, J = 8.5, 4.4 Hz, 1H), 7.35 (dd, J = 5,1.2 Hz, 1H), 7.10 (d, J = 3 Hz, 1H), 6.89 (dd, J = 5, 3 Hz, 1H), 6.32(br s, 2H), 5.08 (t, J = 6 Hz, 2H), 4.02 (q, J = 6 Hz, 2H), 2.92 (t, J =7 Hz, 2H), 1.88 (quintet, J = 7 Hz, 2H), 1.47 (sextet, J = 7 Hz, 2H),0.96 (t, J = 7 Hz, 3H) 141

(CDCl₃) δ 8.45 (dd, J = 4.4, 1.5 Hz, 1H), 8.08 (dd, J = 8.4, 1.5 Hz,1H), 7.43 (dd, J = 8.3, 4.4 Hz, 1H), 7.07 (dd, J = 5, 1.6 Hz, 1H), 6.84(br t, 1H), 6.78 (dd, J = 5, 3.4 Hz, 1H), 6.51 (dd, J = 3, 1 Hz, 1H),6.05 (br s, 2H), 4.94 (t, J = 6 Hz, 2H), 3.82 (q, J = 6 Hz, 2H), 3.49(s, 2H), 2.89 (t, J = 7 Hz, 2H), 1.88 (quintet, J = 7 Hz, 2H), 1.50(sextet, J = 7 Hz, 2H), # 1.00 (t, J = 7 Hz, 3H) 142

(CDCl₃) δ 8.52 (dd, J = 4.4, 1.5 Hz, 1H), 8.42 (br t, 1H), 8.08 (dd, J =8.3, 1.5 Hz, 1H), 8.01 (d, J = 9 Hz, 2H), 7.48 (dd, J = 8.4, 4.4 Hz,1H), 7.39 (d, J = 9 Hz, 2H), 5.80 (br s, 2H), 5.12 (t, J = 6 Hz, 2H),4.05 (q, J = 6 Hz, 2H), 2.94 (t, J = 7 Hz, 2H), 1.93 (quintet, J = 7 Hz,2H), 1.52 (sextet, J = 7 Hz, 2H), 1.01 (t, J = 7 Hz, 3H) 143

(CDCl₃) δ 8.21 (dd, J = 4.4, 1.5 Hz, 1H), 8.05 (dd, J = 8.4, 1.5 Hz,1H), 7.53 (br t, 1H), 7.28 (dd, J = 8.3, 4.4 Hz, 1H), 6.68 (s, 2H), 6.23(br s, 2H), 5.02 (t, J = 6 Hz, 2H), 4.00 (q, J = 6 Hz, 2H), 3.03 (t, J =7 Hz, 2H), 2.21 (s, 3H), 1.99 (s, 6H), 1.94 (quintet, J = 7 Hz, 2H),1.59 (sextet, J = 7 Hz, 2H), 1.03 (t, J = 7 Hz, 3H) 144

(CDCl₃ at 29° C.) δ 8.59 (dd, J = 4.0, 1.5 Hz, 1H), 8.14 (dd, J = 8.0,1.5 Hz, 1H), 8.09 (dd, J = 8, 1.5 Hz, 1H), 7.87 (t, J = 6 Hz, 1H), 7.42(t, J = 8 Hz, 1H), 7.42 (dd, J = 8.0, 4.0 Hz, 1H), 7.06 (t, J = 8 Hz,1H), 6.87 (d, J = 8 Hz, 1H), 6.19 (br s, 2H), 5.07 (t, J = 6 Hz, 2H),4.04 (q, J = 6 Hz, 2H), 3.68 (s, 3H), 2.89 (t, J = 7 Hz, 2H), 1.80 #(quintet, J = 7 Hz, 2H), 1.39 (sextet, J = 7 Hz, 2H), 0.88 (t, J = 7 Hz,3H) 145

(CDCl₃) δ 8.60 (dd, J = 4.4, 1.5 Hz, 1H), 8.11 (dd, J = 8.5, 1.5 Hz,1H), 7.47 (dd, J = 8.5, 4.4 Hz, 1H), 7.01 (br t, 1H), 6.43 (br s, 2H),4.95 (t, J = 6 Hz, 2H), 3.81 (q, J = 6 Hz, 2H), 3.63 (s, 3H), 2.93 (t, J= 7 Hz, 2H), 2.19 (t, J = 7 Hz, 2H), 1.92 (m, 4H), 1.51 (sextet, J = 7Hz, 2H), 1.42 (m, 4H), 1.00 (t, J = 7 Hz, 3H) 146

(CDCl₃) δ 8.23 (dd, J = 4.4, 1.5 Hz, 1H), 8.52 (br s, 1H), 8.10 (dd, J =8.5, 1.5 Hz, 1H), 7.53 (dd, J = 8.3, 4.4 Hz, 1H), 7.21 (d, J = 4 Hz,1H), 7.06 (d, J = 4 Hz, 1H), 6.1 (br s, 2H), 5.11 (t, J = 6 Hz, 2H),4.04 (q, J = 6 Hz, 2H), 2.94 (t, J = 7 Hz, 2H), 1.93 (quintet, J = 7 Hz,2H), 1.53 (sextet, J = 7 Hz, 2H), 1.01 (t, J = 7 Hz, 3H) 147

(CDCl₃) δ 8.39 (dd, J = 4.4, 1.5 Hz, 1H), 8.31 (dd, J = 5.0, 2 Hz, 1H),8.21 (br t, J = 6 Hz, 1H), 8.00 (dd, J = 8.4, 1.5 Hz, 1H), 7.42 (dd, J =5, 8 Hz, 1H), 7.33 (dd, J = 8.5, 4.4 Hz, 1H), 7.07 (dd, J = 8, 5 Hz,1H), 5.84 (br s, 2H), 5.06 (t, J = 6 Hz, 2H), 4.05 (q, J = 6 Hz, 2H),2.97 (t, J = 7 Hz, 2H), 1.93 (quintet, J = 7 Hz, 2H), 1.53 # (sextet, J= 7 Hz, 2H), 1.01 (t, J = 7 Hz, 3H) 148

(CDCl₃ at 60° C.) δ 8.54 (dd, J = 4.4, 1.5 Hz, 1H), 8.33 (d, J = 2 Hz,1H), 8.06 (dd, J = 8.4, 1.5 Hz, 1H), 8.06 (br s, 1H), 7.56 (dd, 8.5, 2Hz, 1H), 7.45 (dd, J = 8.4, 4.4 Hz, 1H), 7.15 (d, J = 8 Hz, 1H), 5.72(br s, 2H), 5.08 (t, J = 6 Hz, 2H), 4.03 (q, J = 6 Hz, 2H), 2.93 (t, J =7 Hz, 2H), 1.93 (quintet, J = 7 Hz, 2H), 1.52 sextet, J = 7 Hz, 2H ,1.00 (t, J = 7 Hz, 3H) 149

(CDCl₃) δ 8.61 (dd, J = 4.4, 1.5 Hz, 1H), 8.03 (dd, J = 8.3, 1.5 Hz,1H), 7.50 (t, J = 6 Hz, 1H), 7.44 (dd, J = 8.3, 4.4 Hz, 1H), 7.42 (d, J= 8 Hz, 2H), 6.73 (d, J = 8 Hz, 2H), 6.45 (br s, 2H), 5.06 (t, J = 6 Hz,2H), 4.00 (q, J = 6 Hz, 2H), 3.90 (t, J = 7 Hz, 2H), 2.90 (t, J = 7 Hz,2H), 1.84 (quintet, J = 7 Hz, 2H), 1.74 (quintet, J = 7 Hz, 2H), # 1.42,m, 4H), 1.28 (m, 6H), 0.93 (t, J = 7 Hz, 3H), 0.87 (t, 3H) 150

(CDCl₃) δ 8.61 (dd, J = 4.4, 1.5 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.90(d, J = 8 Hz, 2H), 7.84 (br s, 1H), 7.48 (dd, J = 8.5, 4.4 Hz, 1H), 7.44(d, J = 8 Hz, 2H), 6.4 (br s, 2H), 5.12 (t, J = 6 Hz, 2H), 3.94 (t, J =7 Hz, 2H), 3.91 (s, 3H), 2.94 (t, J = 7 Hz, 2H), 1.91 (quintet, J = 7Hz, 2H), 1.50 (sextet, J = 7 Hz, 2H), 0.99 (t, J = 7 Hz, 3H) 151

(CDCl₃) δ 8.48 (br s, 1H), 8.22 (dd, J = 4.5, 1.5 Hz, 1H), 8.04 (dd, J =8.4, 1.5 Hz, 1H), 7.33 (s, 2H), 7.30 (dd, J = 8.4, 4.4 Hz, 1H), 5.96 (brs, 2H), 5.00 (t, J = 6 Hz, 2H), 4.03 (q, J = 6 Hz, 2H), 2.99 (t, J = 7Hz, 2H), 1.93 (quintet, J = 7 Hz, 2H), 1.54 (sextet, J = 7 Hz, 2H), 1.03(t, J = 7 Hz, 3H) 152

(CDCl₃) δ 8.41 (dd, J = 4.4, 1.5 Hz, 1H), 8.06 (dd, J = 8.3, 1.5 Hz,1H), 7.41 (dd, J = 8.5, 4.4 Hz, 1H), 6.75 (d, J = 8 Hz, 2H), 6.64 (d, J= 8 Hz, 2H), 6.60 (br t, 1H), 6.02 (br s, 2H), 4.92 (t, J = 6 Hz, 2H),3.80 (q, J = 4.6 Hz, 2H), 3.76 (s, 3H), 3.22 (s, 2H), 2.88 (t, J = 7 Hz,2H), 1.87 (quintet, J = 7 Hz, 2H), 1.50 (sextet, J = 7 Hz, 2H), 1.00 (t,J = 7 Hz, 3H)

EXAMPLES 153-190 Compounds of Formula I

[0453] The compounds of Examples 153-190 shown in the table below wereprepared according to the following method.4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butaneamine(25 μmol) was dissolved in dichloromethane (10 mL) in a screw-cappedtest tube and the solution was cooled in an ice-water bath. An acidchloride (25 μmol) of the formula R_(A)COCl was added as a solution in100 μL of dichloromethane (Acid chlorides that are solids were addeddirectly.). The mixture was vortexed for 15 seconds to 1 minute,becoming cloudy, and then 80 mg of an aminomethyl polystyrene resin(0.62 meq/g, 100-200 mesh, 1% crosslink, Bachem #D-2100, lot # FM507)was added, and the mixture was vortexed for another 30 seconds. Themixture was applied to a short column (3×1 cm) of silica gel conditionedwith dichloromethane. The product was eluted with 10:1dichloromethane:methanol, collecting ˜2 mL fractions. Thin layerchromatography of the fractions was performed, and fractions with theproduct spot were pooled and stripped to dryness in a Savant SpeedVac.Purity was checked by reversed phase-HPLC (HPLC conditions refer tousing a Hewlett Packard HP 1090 system fitted with a C18 RaininMicrosorb MV column, 4.6×50 mm, particle size=3 microns, pore size=1001Angstroms. Gradient elution: linear gradient from 100% water+0.1%trifluoroacetic acid to 100% acetonitrile+0.1% trifluoroacetic acid over5 min. at 1 mL per minute. Detection is at 220 nm and 254 nm). APCI-massspectral data confirmed presence of the expected molecular ion, andproton nmr data supported the expected structure.

Example # R_(A) Fragment ¹−H NMR (500 MHz, solvent indicated) 153

(CDCl₃ at 29° C.) δ 8.53 (dd, J = 4.4, 1.5 Hz, 1H), 8.12 (dd, J = 8.5,1.5 Hz, 1H), 7.83 (t, J = 2 Hz, 1H), 7.59 (d, J = 8 Hz, 1H), 7.57 (d, J= 8 Hz, 1H), 7.42 (dd, J = 8.5, 4.4 Hz, 1H), 7.23 (t, J = 8 Hz, 1H),6.73 (t, J = 6 Hz, 1H), 6.50 (br s, 2H), 4.84 (t, J = 6 Hz, 2H), 3.60(q, J = 6 Hz, 2H), 2.92 (t, J = 7 Hz, 2H), 2.04 (quintet, # J = 7 Hz,2H), 1.88 (quintet, J = 7 Hz, 2H), 1.80 (m, J = 7 Hz, 2H), 1.48 (m, 2H),0.99 (t, J = 7 Hz, 3H) 154

(CDCl₃ at 29° C.) δ 8.60 (dd, J = 4.4, 1.5 Hz, 1H), 8.09 (dd, J = 8.5,1.5 Hz, 1H), 7.43 (dd, J = 8.5, 4.4 Hz, 1H), 6.32 (br s, 2H), 5.75 (t, J= 6 Hz, 1H), 4.81 (t, J = 6 Hz, 2H), 3.35 (q, J = 6 Hz, 2H), 2.91 (t, J= 7 Hz, 2H), 2.1-1.6 (m, ca. 21H), 1.51 (sextet, J = 7 Hz, 2H), 1.01 (t,J = 7 Hz, 3H) 155

(CDCl₃ at 60° C.) δ 8.44 (dd, J = 4.4, 1.5 Hz, 1H), 8.10 (dd, J = 8.5,1.5 Hz, 1H) 7.43 (dd, J = 8.5, 4.4 Hz, 1H), 7.10 (s, 4H), 6.00 (br s,2H), 5.60 (t, J = 6 Hz, 1H), 4.63 (t, J = 6 Hz, 2H), 3.30 (q, J = 6 Hz,2H), 2.86 (t, J = 7 Hz, 2H), 2.37 (m, 2H), 2.0-1.4 (m, 14H), 1.01 (t, J= 7 Hz, 3H) 156

(CDCl₃ at 60° C.) δ 8.33 (d, J = 4.4 Hz, 1H), 8.08 (dd, J = 8.5, 1.5 Hz,1H), 7.5-7.0 (m, 4H), 6.70 (br s, 1H), 6.25 (br s, 2H), 4.85 (t, J = 6Hz, 2H), 3.67 (q, J = 6 Hz, 2H), 2.93 (t, J = 7 Hz, 2H), 2.08 (quintet,J = 7 Hz, 2H), 1.89 (m, 4H), 1.53 (sextet, J = 7 Hz, 2H), 1.02 (t, J = 7Hz, 3H) 157

(CDCl₃ at 60° C.) δ 8.59 (dd, J = 4.4, 1.5 Hz, 1H), 8.10 (dd, J = 8.5,1.5 Hz, 1H), 7.40 (dd, J = 8.5, 4.4 Hz, 1H), 7.28 (m, 3H), 7.21 (m, 2H),6.84 (t, J = 6 Hz, 1H), 6.4 (br s, 2H), 4.81 (t, J = 6 Hz, 2H), 4.49 (s,2H), 3.96 (s, 2H), 3.42 (q, J = 6 Hz, 2H), 2.91 (t, J = 7 Hz, 2H), 1.95(quintet, J = 7 Hz, 2H), 1.90 (quintet, # J = 7 Hz, 2H), 1.69 (quintet,J = 7 Hz, 2H), 1.51 (sextet, J = 7 Hz, 2H), 1.01 (t, J = 7 Hz, 3H) 158

(d₆-DMSO at 29° C.) δ 8.50 (dd, J = 4.4, 1.5 Hz, 1H), 7.91 (dd, J = 8,1.5 Hz, 1H), 7.71 (t, J = 6 Hz, 1H), 7.43 (dd, J = 8.4, 4,4 Hz, 1H),6.80 (br s, 2H), 4.79 (t, J = 6 Hz, 2H), 3.57 (s, 3H), 3.05 (q, J = 6Hz, 2H), 2.28 (q, J = 7 Hz, 4H), 2.20 (t, J = 7 Hz, 2H), 1.98 (t, J = 7Hz, 2H), 1.80 (m, 4H), 1.6-1.1 (m, 14H), 0.96 (t, J = 7 Hz, 3H) 159

(d₆-DMSO at 29° C.) δ 8.51 (dd, J = 4.4, 1.5 Hz, 1H), 7.92 (dd, J = 8.5,4.4 Hz, 1H), 7.72 (t, J = 6 Hz, 1H), 7.43 (dd, J = 8.5, 4.4 Hz, 1H),6.86 (br s, 2H), 5.77 (m, 1H), 4.98 (dd, J = Hz, 1H), 4.92 (m, 1H), 4.79(t, J = 6 Hz, 2H), 3.08 (q, J = 6 Hz, 2H), 2.94 (t, J = 7 Hz, 2H), 1.98(quintet, J = 7 Hz, 2H), 1.80 (m, 2H), 1.55-1.1 (m, 20 H), 0.96 (t, J =7 Hz, 3H) 160

(d₆-DMSO at 29° C.) δ 8.49 (dd, J = 4.4, 1.5 Hz, 1H), 7.90 (dd, J = 8.2,1.5 Hz, 1H), 7.71 (t, J = 6 Hz, 1H), 7.42 (dd, J = 8.2, 4.4 Hz, 1H),6.74 (br s, 2H), 4.79 (t, J = 6 Hz, 2H), 3.06 (q, J = 6 Hz, 2H), 2.92(t, J = 7 Hz, 2H), 2.04 (m, 1H), 1.96 (m, 2H), 1.82 (m, 4H), 1.6-1.3 (m,10H), 1.04 (m, 2H), 0.96 (t, J = 7 Hz, 3H) 161

(d₆-DMSO at 29° C.) δ 8.95 (t, J = 6 Hz, 1H), 8.44 (m, 3H), 8.31 (s,1H), 7.88 (dd, J = 8.5, 1.5 Hz, 1H), 7.37 (dd, J = 8.5, 4.4 Hz, 1H),6.76 (s, 2H), 4.82 (t, J = 6 Hz, 2H), 3.38 (m, 2H, 2.91 (t, J = 7 Hz,2H), 1.90 (m, 2H), 1.76 (m, 2H), 1.64 (m, 2H), 1.39 (m, 2H), 0.86 (t, J= 7 Hz, 3H) 162

(d₆-DMSO at 29° C.) δ 8.44 (dd, J = 4.4, 1.5 Hz, 1H), 8.39 (t, J = 6 Hz,1H), 7.89 (dd, J = 8.2, 1.5 Hz, 1H), 7.39 (dd, J = 8.2, 4.4 Hz, 1H),7.12 (s, 2H), 6.75 (br s, 2H), 4.81 (t, J = 6 Hz, 2H), 3.78 (s, 6H),3.68 (s, 3H), 3.32 (m, 2H), 2.92 (m, 2H), 1.90 (m, 2H), 1.80 (m, 2H),1.60 (m, 2H), 1.40 (sextet, J = 7 Hz, 2H), 0.91 (t, J = 7 Hz, 3H) 163

(d₆-DMSO at 29° C.) δ 8.89 (t, J = 6 Hz, 1H), 8.51 (dd, J = 4.4, 1.5 Hz,1H), 7.93 (d, J = 8.5 Hz, 1H), 7.44 (dd, J = 8.5, 4.4 Hz, 1H), 6.95 (brs, 2H), 4.83 (t, J = 6 Hz, 2H), 3.34 (m, 2H), 2.95 (t, J = 7 Hz, 2H),2.90 (m, 2H), 2.85 (m, 2H), 1.60 (quintet, J = 7 Hz, 2H), 1.45 (m, 2H),0.96 (t, J = 7 Hz, 3H) 164

(d₆-DMSO at 29° 0.) δ 8.50 (dd, J = 4.3, 1.5 Hz, 1H), 8.38 (t, J = 6 Hz,1H), 7.91 (dd, J = 8.4, 1.5 Hz, 1H), 7.44 (dd, J = 8, 1 Hz, 1H), 7.39(dt, J = 8, 1 Hz, 1H), 7.43 (dd, J = 8.4, 4.3 Hz, 1H), 7.31 (dt (J = 8,1 Hz, 1H), 7.27 (dd, J = 8, 1 Hz, 1H), 6.74 (s, 2H), 4.83 (t, J = 6 Hz,2H), 3.26 (q, J = 6 Hz, 2H), 2.94 (t, J = 7 Hz, 2H), 1.95 (m, 2H), #1.83 (m, 2H), 1.60 (quintet, J = 7 Hz, 2H), 1.45 (m, 2H), 0.95 (t, J = 7Hz, 3H) 165

(d₆-DMSO at 29° C.) δ 8.49 (dd, J = 4.3, 1.5 Hz, 1H), 8.44 (t, J = 6 Hz,1H), 7.91 (dd, J = 8.2, 1.5 Hz, 1H), 7.64 (d, J = 2 Hz, 1H), 7.43 (dd, J= 8.2, 4.3 Hz, 1H), 7.42 (dd, J = 8, 2 Hz, 1H), 7.30 (d, J = 8 Hz, 1H),6.75 (br s, 2H), 4.82 (t, J = 6 Hz, 2H), 3.25 (q, J = 6 Hz, 2H), 2.93(t, J = 7 Hz, 2H), 1.90 (m, 2H), 1.82 (m, 2H), 1.60 (m, 2H), 1.45 #(sextet, J = 7 Hz, 2H), 0.95 (t, J = 7 Hz, 3H) 166

(d₆-DMSO at 29° C.) δ 8.46 (dd, J = 4.3, 1.5 Hz, 1H), 8.46 (m, 1H), 7.89(dd, J = 8.5, 1.5 Hz, 1H), 7.84 (dd, J = 8, 5 Hz, 2H), 7.40 (dd, J =8.5, 4.3 Hz, 1H), 7.26 (t, J = 9 Hz, 2H), 6.74 (br s, 2H), 4.81 (t, J =6 Hz, 2H), 3.31 (q, J = 6 Hz, 2H), 2.91 (t, J = 7 Hz, 2H), 1.88 (m, 2H),1.79 (m, 2H), 1.60 (quintet, J = 7 Hz, 2H), 1.45 (m, 2H), 0.91 (t, J = 7Hz, 3H) 167

(d₆-DMSO at 29° C.) δ 8.53 (t, J = 6 Hz, 1H), 8.46 (dd, J = 4.4, 1.5 Hz,1H), 7.89 (dd, J = 8.5, 1.5 Hz, 1H), 7.79 (d, J = 8 Hz, 2H), 7.50 (d, J= 8.5 Hz, 2H), 7.40 (dd, J = 8.5, 4.3 Hz, 1H), 6.74 (s, 2H), 4.81 (t, J= 6 Hz, 2H), 3.30 (q, J = 6 Hz, 2H), 2.91 (t, J = 7 Hz, 2H), 1.92 (m,2H), 1.78 (quintet, J = 7 Hz, 2H), 1.60 (quintet, J = 7 Hz, 2H), # 1.40(sextet, J = 7 Hz, 2H), 0.90 (t, J = 7 Hz, 3H) 168

(d₆-DMSO at 29° C.) δ 8.47 (dd, J = 4.3, 1.5 Hz, 1H), 8.29 (t, J = 6 Hz,1H), 7.89 (dd, J = 8.5, 1.5 Hz, 1H), 7.76 (d, J = 8 Hz, 2H), 7.40 (dd, J= 8.5, 4.3 Hz, 1H), 6.96 (d, J = 8 Hz, 2H), 6.74 (s, 2H), 4.81 (t, J = 6Hz, 2H), 3.79 (s, 3H), 3.39 (q, J = 6 Hz, 2H), 2.91 (t, J = 7 Hz, 2H),1.86 (m, 2H), 1.79 (quintet, J = 7 Hz, 2H), 1.60 (quintet, # J = 7 Hz,2H), 1.41 (sextet, J = 7 Hz, 2H), 0.91 (t, J = 7 Hz, 3H) 169

(d₆-DMSO at 29° C.) δ 8.67 (t, J = 6 Hz, 1H), 8.46 (dd, J = 4.0, 1.5 Hz,1H), 7.97 (d, J = 8 Hz, 2H), 7.89 (dd, J = 8, 1.5 Hz, 1H), 7.39 (dd, J =8, 1.5 Hz, 1H), 7.38 (d, J = 8 Hz, 2H), 6.74 (s, 2H), 4.82 (t, J = 6 Hz,2H), 3.32 (m, 2H), 2.91 (t, J = 7 Hz, 2H), 1.89 (m, 2H), 1.78 (quintet,J = 7 Hz, 2H), 1.62 (quintet, J = 7 Hz, 2H), 1.40 (sextet, # J = 7 Hz,2H), 0.89 (t, J = 7 Hz, 3H) 170

(d₆-DMSO at 29° C.) δ 8.46 (dd, J = 4.0, 1.5 Hz, 1H), 8.35 (t, J = 6 Hz,1H), 7.89 (dd, J = 8.5, 1.5 Hz, 1H), 7.71 (d, J = 8 Hz, 2H), 7.43 (d, J= 8 Hz, 2H), 7.40 (dd, J = 8, 4.0 Hz, 1H), 6.73 (s, 2H), 4.80 (t, J = 6Hz, 2H), 3.30 (q, J = 6 Hz, 2H), 2.91 (t, J = 7 Hz, 2H), 1.88 (quintet,J = 7 Hz, 2H), 2.80 (quintet, J = 7 Hz, 2H), 1.60 (m, 2H), 1.39 (sextet,# J = 7 Hz, 2H), 1.29 (s, 9H), 0.90 (t, J = 7 Hz, 3H) 171

(d₆-DMSO at 29° C.) δ 8.47 (dd, J = 4.0, 1.5 Hz, 1H), 8.35 (t, J = 6 Hz,1H), 7.89 (dd, J = 8.0, 1.5 Hz, 1H), 7.69 (d, J = 8 Hz, 2H), 7.40 (dd, J= 8.0, 4.0 Hz, 1H), 7.23 (d, J = 8 Hz, 2H), 6.74 (s, 2H), 4.81 (t, J = 6Hz, 2H), 3.28 (q, J = 6 Hz, 2H), 2.91 (t, J = 7 Hz, 2H), 2.34 (s, 3H),2.90 (m, 2H), 1.79 (quintet, J = 7 Hz, # 2H), 1.60 (quintet, J = 7 Hz,2H), 1.41 (sextet, J = 7 Hz, 2H), 0.91 (t, J = 7 Hz, 3H) 172

(d₆-DMSO at 29° C.) δ 8.49 (dd, J = 4.5, 1.5 Hz, 1H), 7.90 (dd, J = 8.5,1.5 Hz, 1H), 7.67 (t, J = 6 Hz, 1H), 7.42 (dd, J = 8.5, 4.5 Hz, 1H),6.74 (s, 2H), 4.79 (t, J = 6 Hz, 2H), 3.06 (q, J = 6 Hz, 2H), 2.91 (t, J= 7 Hz 2H), 1.87 (s, 2H), 1.82 (quintet, J = 7 Hz, 4H), 1.46 (sextet, J= 7 Hz, 4H), 0.96 (t, J = 7 Hz, 3H), 0.86 (s, 9H) 173

(d₆-DMSO at 29° C.) δ 8.50 (dd, J = 4.5, 1.5 Hz, 1H), 8.00 (t, J = 6 Hz,1H), 7.90 (dd, J = 8.5, 1.5 Hz, 1H), 7.43 (dd, J = 8.5, 4.5 Hz, 1H),6.75 (s, 2H), 4.79 (t, J = 6 Hz, 2H), 3.10 (q, J = 6 Hz, 2H), 2.92 (t, J= 7 Hz, 2H), 1.82 (m, 4H), 1.45 (m, 5H), 0.94 (t, J = 7 Hz; 3H), 0.60(m, 4H) 174

(d₆-DMSO at 29° C.) δ 8.49 (dd, J = 4.3, 1.5 Hz, 1H), 7.90 (dd, J = 8.4,1.5 Hz, 1H), 7.68 (t, J = 6 Hz, 1H), 7.42 (dd, J = 8.4, 4.3 Hz, 1H),6.73 (br s, 2H), 4.80 (t, J = 6 Hz, 2H), 3.06 (q, J = 6 Hz, 2H), 2.92(t, J = 7 Hz, 2H), 2.44 (m, 1H), 1.81 (m, 4H), 1.70-1.30 (m, 12H), 0.96(t, J = 7 Hz, 3H) 175

(d₆-DMSO at 29° C.) δ 8.50 (dd, J = 4.5, 1.5 Hz, 1H), 7.90 (dd, J = 8.0,1.5 Hz, 1H), 7.73 (t, J = 6 Hz, 1H), 7.42 (dd, J = 8.0, 4.5 Hz, 1H),6.75 (s, 2H), 4.78 (t, J = 6 Hz, 2H), 3.06 (q, J = 6 Hz, 2H), 2.92 (t, J= 7 Hz, 2H), 1.99 (t, J = 7 Hz, 2H), 1.81 (m, 4H), 1.63 (m, 3H), 1.6-1.3(m, 10H), 1.00 (m, 2H), 0.97 (t, J = 7 Hz, 3H) 176

(d₆-DMSO at 29° C.) δ 8.69 (t, J = 6 Hz, 1H), 8.45 (dd, J = 4.3, 1.5 Hz,1H), 7.91 (m, 4H), 7.89 (dd, J = 8.3, 1.5 Hz, 1H), 7.40 (dd, J = 8.3,4.3 Hz, 1H), 6.74 (s, 2H), 4.81 (t, J = 6 Hz, 2H), 3.31 (m, 2H), 2.91(t, J = 7 Hz, 2H), 1.90 (m, 2H), 1.79 (quintet, J = 7 Hz, 2H), 1.60 (m,2H), 1.40 (sextet, J = 7 Hz, 2H), 0.90 (t, J = 7 Hz, 3H) 177

(d₆-DMSO at 29° C.) δ 8.46 (dd, J = 4.3, 1.5 Hz, 1H), 8.45 (t, J = 6 Hz,1H), 7.89 (dd, J = 8.4, 1.5 Hz, 1H), 7.72 (dd, J = 5, 1 Hz, 1H), 7.67(dd, J = 3, 1 Hz, 1H), 7.40 (dd, J = 8.4, 4.3 Hz, 1H), 7.11 (dd, J = 5,3 Hz, 1H), 6.74 (s, 2H), 4.82 (t, J = 6 Hz, 2H), 3.28 (q, J = 6 Hz, 2H),2.92 (t, J = 7 Hz, 2H), 1.87 (m, 2H), # 1.79 (quintet, J = 7 Hz, 2H),1.60 (quintet, J = 7 Hz, 2H), 1.42 (sextet, J = 7 Hz, 2H), 0.91 (t, J =7 Hz, 3H) 178

(d₆-DMSO at 29° C.) δ 8.49 (dd, J = 4.3, 1.5 Hz, 1H), 8.05 (t, J = 6 Hz,1H), 7.91 (dd, J = 8.2, 1.5 Hz, 1H), 7.43 (dd, J = 8.2, 4.3 Hz, 1H),7.29 (dd, J = 5, 1 Hz, 1H), 6.89 (dd, J = 5, 3 Hz, 1H), 6.82 (dd, J = 3,1 Hz, 1H), 6.77 (br s, 2H), 4.79 (t, J = 6 Hz, 2H), 3.56 (s, 2H), 3.09(q, J = 6 Hz, 2H), 2.90 (t, J = 7 Hz, 2H), 1.75 (m, 4H), 1.45 (m, 4H),0.95 (t, J = 7 Hz, 3H) 179

(d₆-DMSO at 29° C.) δ 8.77 (t, J = 6 Hz, 1H), 8.46 (dd, J = 4.4, 1.5 Hz,1H), 8.28 (dd, J = 8.5, 2.5 Hz, 2H), 8.00 (dd, J = 8.5 2.5 Hz, 2H), 7.89(dd, J = 8.3, 1.5 Hz, 1H), 7.39 (dd, J = 8.3, 4.4 Hz, 1H), 6.75 (s, 2H),4.82 (t, J = 6 Hz, 2H), 3.32 (m, 2H), 2.92 (t, J = 7 Hz, 2H), 1.90 (m,2H), 1.79 (quintet, J = 7 Hz, 2H), 1.63 (m, 2H), 1.42 (sextet, # J = 7Hz, 2H), 0.91 (t, J = 7 Hz, 3H) 180

(d₆-DMSO at 29° C.) δ 8.48 (dd, J = 4.3, 1.5 Hz, 1H), 8.14 (t, J = 6 Hz,1H), 7.91 (dd, J = 8.4, 1.5 Hz, 1H), 7.42 (dd, J = 8.4, 4.3 Hz, 1H),6.78 (s, 2H), 6.75 (br s, 2H), 4.82 (t, J = 6 Hz, 2H), 3.22 (q, J = 6Hz, 2H), 2.92 (t, J = 7 Hz, 2H), 2.50 (s, 3H), 2.03 (s, 6H), 1.90 (m,2H), 1.85 (quintet, J = 7 Hz, 2H), 1.58 (m, 2H), 1.45 (sextet, # J = 7Hz, 2H), 0.96 (t, J = 7 Hz, 3H) 181

(d₆-DMSO at 29° C.) δ 9.48 (t, J = 6 Hz, 1H), 8.52 (d, J = 4.3 Hz, 1H),7.94 (d, J = 8 Hz, 1H), 7.45 (dd, J = 8.0, 4.3 Hz, 1H), 7.09 (br s, 2H),4.80 (t, J = 6 Hz, 2H), 3.25 (q, J = 6 Hz, 2H), 2.92 (t, J = 7 Hz, 2H),1.81 (m, 4H), 1.58 (m, 2H), 1.45 (sextet, J = 7 Hz, 2H), 0.95 (t, J = 7Hz, 3H) 182

(d₆-DMSO at 29° C.) δ 8.50 (dd, J = 4.3, 1.5 Hz, 1H), 7.90 (dd, J = 8.0,1.5Hz, 1H), 7.75 (t, J = 6 Hz, 1H), 7.42 (dd, J = 8.0, 4.3 Hz, 1H), 6.77(br s, 2H), 4.78 (t, J = 6 Hz, 2H), 3.56 (s, 3H), 3.06 (q, J = 6 Hz,2H), 2.90 (t, J = 7 Hz, 2H), 2.25 (m, 2H), 2.00 (m, 2H), 1.81 (m, 4H),1.44 (m, 8H), 0.96 (t. J = 7 Hz, 3H) 183

(d₆-DMSO at 29° C.) δ 8.55 (t, J = 6 Hz, 1H), 8.50 (dd, J = 4.3, 1.5 Hz,1H), 8.43 (dd, J = 5, 2 Hz, 1H), 7.91 (dd, J = 8.4, 1.5 Hz, 1H), 7.74(d, J = 8.0, 2 Hz, 1H), 7.43 (dd, J = 8, 4.3 Hz, 1H), 7.42 (dd, J = 8, 5Hz, 1H), 6.75 (br s, 2H), 4.83 (t, J = 6 Hz, 2H), 3.27 (q, J = 6 Hz,2H), 2.94 (t, J = 7 Hz, 2H), 1.92 (m, 2H), 1.83 (quintet, # J = 7 Hz,2H), 1.60 (m, 2H), 1.46 (sextet, J = 7 Hz, 2H), 0.95 (t, J = 7 Hz, 3H)184

(d₆-DMSO at 29° C.) δ 8.77 (dd, J = 2.5, 0.5 Hz, 1H), 8.70 (t, J = 6 Hz,1H), 8.46 (dd, J = 4.3, 1.5 Hz, 1H), 8.16 (dd, J = 8, 3 Hz, 1H), 7.91(dd, J = 8.4, 1.5 Hz, 1H), 7.62 (dd, J = 8, 0.5 Hz, 1H), 7.43 (dd, J =8.4, 1.5 Hz, 1H), 6.76 (br s, 2H), 4.81 (t, J = 6 Hz, 2H), 3.31 (m, 2H),2.92 (t, J = 7 Hz, 2H), 1.89 (m, 2H), 1.79 (quintet, J = 7 Hz, 2H), 1.61# (quintet, J = 7 Hz, 2H), 1.40 (sextet, J = 7 Hz, 2H), 0.91 (t, J = 7Hz, 3H) 185

(d₆-DMSO at 29° C.) δ 8.55 (t, J = 6 Hz, 1H), 8.45 (dd, J = 4.3, 1.5 Hz,1H), 7.90 (d, J = 8 Hz, 2H), 7.89 (dd, J = 8, 1.5 Hz, 1H), 7.43 (d, J =8 Hz, 2H), 7.39 (dd, J = 8, 4.3 Hz, 1H), 6.74 (br s, 2H), 4.81 (t, J = 6Hz, 2H), 3.30 (m, 2H), 2.91 (t, J = 7 Hz, 2H), 1.88 (m, 2H), 1.78(quintet, J = 7 Hz, 2H), 1.63 (m, 2H), 1.34 (sextet, J = 7 Hz, 2H), 0.89(t, J = 7 Hz, 3H) 186

(d₆-DMSO at 29° C.) δ 8.64 (t, J = 6 Hz, 1H), 8.49 (dd, J = 4.4, 1.5 Hz,1H), 7.90 (dd, J = 8.5, 1.5 Hz, 1H), 7.69 (s, 2H), 7.42 (dd, J = 8.5,4.3 Hz, 1H), 6.74 (s, 2H), 4.84 (t, J = 6 Hz, 2H), 3.26 (q, J = 6 Hz,2H), 2.93 (t, 1 = 7 Hz, 2H), 1.90 (m, 2H), 1.83 (quintet, J = 7 Hz, 2H),1.60 (m, 2H), 1.46 (sextet, J = 7 Hz, 2H), 0.96 (t, J = 7 Hz, 3H) 187

(d₆-DMSO at 29° C.) δ 8.49 (dd, J = 4.3, 1.5 Hz, 1H), 7.92 (t, J = 6 Hz,1H), 7.90 (dd, J = 8.5, 1.5 Hz, 1H), 7.42 (dd, J = 8.5, 4.3 Hz, 1H),7.07 (d, J = 8 Hz, 2H), 6.76 (d, J = 8 Hz, 2H), 6.74 (br s, 2H), 4.79(t, J = 6 Hz, 2H), 3.70 (s, 3H),nl 3.25 (s, 2H), 3.08 (q, J = 6 Hz, 2H),2.89 (t, J = 7 Hz, 2H), 1.80 (m, 4H), 1.46 (m, 2H), 1.44 (sextet, J = 7Hz, 2H), 0.95 (t, J = 7 Hz, 3H) 188

(d₆-DMSO at 29° C.) δ 8.47 (dd, J = 4.3, 1.5 Hz, 1H), 8.15 (t, J = 6 Hz,1H), 7.90 (dd, J = 8.4, 1.5 Hz, 1H), 7.64 (dd, J = 8, 2 Hz, 1H), 7.41(dt, J = 8, 2 Hz, 1H), 7.40 (dd, J = 8.4, 4.3 Hz, 1H), 7.06 (d, J = 8Hz, 1H), 6.98 (dt, J = 8, 2 Hz, 1H), 6.74 (s, 2H), 4.82 (t, J = 6 Hz,2H), 3.70 (s, 3H), 3.33 (m, 2H), 2.92 (t, J = 7 Hz, 2H), 1.90 (m, 2H),1.8 (quintet, # J = 7 Hz, 2H), 1.60 (m, 2H), 1.43 (sextet, J = 7 Hz,2H), 0.92 (t, J = 7 Hz, 3H) 189

(d₆-DMSO at 29° C.) δ 8.56 (t, J = 6 Hz, 1H), 8.46 (dd, J = 4.4, 1.5 Hz,1H), 7.89 (dd, J = 8.4, 1.5 Hz, 1H), 7.82 (t, J = 2 Hz, 1H), 7.74 (td, J= 8,2 Hz, 1H), 7.58 (td, J = 8,2 Hz, 1H), 7.47 (t, J = 8 Hz, 1H), 7.39(dd, J = 8.4, 4.4 Hz, 1H), 6.74 (s, 2H), 4.81 (t, J = 6 Hz, 2H), 3.31(q, J = 6 Hz, 2H), 2.91 (t, J = 7 Hz, 2H), 1.88 (m, 2H), 1.79 (quintet,# J = 7 Hz, 2H), 1.61 (m, 2H), 1.36 (sextet, J = 7 Hz, 2H), 0.90 (t, J =7 Hz, 3H) 190

(d₆-DMSO at 29° C.) δ 8.46 (dd, J = 4.3, 1.5 Hz, 1H), 8.27 (t, J = 6 Hz,1H), 7.89 (dd, J = 8.5, 1.5 Hz, 1H), 7.75 (d, J = 8 Hz, 2H), 7.40 (dd, J= 8.5, 4.3 Hz, 1H), 6.94 (d, J = 8 Hz, 2H), 6.73 (s, 2H), 4.81 (t, J = 6Hz, 2H), 4.00 (t, J = 7 Hz, 2H), 3.28 (q, J = 6 Hz, 2H), 2.91 (t, J = 7Hz, 2H), 1.87 (m, 2H), 1.78 (quintet, J = 7 Hz, 2H), 1.71 (quintet, # J= 7 Hz, 2H), 1.60 (m, 2H), 1.38 (sextet, J = 7 Hz, 4H), 1.32 (m, 2H),1.28 (m, 4H), 0.91 (t, J = 7 Hz, 3H), 0.87 (t, J = 7 Hz, 3H)

EXAMPLES 191-212 Compounds of Formula I

[0454] The compounds of Examples 191-212 shown in the table below wereprepared according to the following method.4-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(50 μmol) was dissolved in 5 mL of dichloromethane in a screw-cappedtest tube and a carboxylic acid (50 μmol) of formula R_(A)COOH was addedat ambient temperature. Within 3 minutes a light suspension typicallyformed. The coupling agent, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (˜10.5 mg, 55 μmol) was added and the mixturewas vortexed at 400 rpm for 1-2 h at ambient temperature, giving a clearsolution in most cases. The mixture was applied to a short column (3×1cm) of silica gel conditioned with dichloromethane. The product waseluted with 10:1 dichloromethane:methanol, collecting ˜2 mL fractions.Thin layer chromatography of the fractions was performed, and fractionswith the product spot were pooled and stripped to dryness in a SavantSpeedVac. Purity was checked by reversed phase-HPLC (HPLC conditionsrefer to using a Hewlett Packard HP 1090 system fitted with a C18 RaininMicrosorb MV column, 4.6×50 mm, particle size=3 microns, pore size=100Angstroms. Gradient elution: linear gradient from 100% water+0.1%trifluoroacetic acid to 100% acetonitrile+0.1% trifluoroacetic acid over5 min. at 1 mL per minute. Detection is at 220 nm and 254 nm). APCI-massspectral data confirmed presence of the expected molecular ion, andproton nmr data supported the expected structure.

Example # R_(A) Fragment ¹H NMR (500 MHz, solvent indicated) 191

(CDCl₃) δ 8.47 (dd, J = 4.4, 1.5 Hz, 1H), 8.10 (dd, J = 8.5, 1.5 Hz,1H), 7.45 (dd, J = 8.5, 4.4 Hz, 1H), 7.15 (dd, J = 5.0, 3.0 Hz, 1H),6.75 (d, J = 3 Hz, 1H), 6.64 (dd, J = 5.0, 1.2 Hz, 1H), 6.61 (br t, 1H),6.3 (br s, 2H), 4.94 (t, J = 6 Hz, 2H), 3.30 (s, 2H), 2.81 (q, J = 6 Hz,2H), 2.89 (t, J = 7 Hz, 2H), 1.88 (quintet, J = 7 Hz, 2H), 1.50 (sextet,J = 7 Hz, 2H), # 1.00 (t, J = 7 Hz, 3H) 192

(CDCl₃) δ 8.41 (dd, J = 4.4, 1.5 Hz, 1H), 8.04 (dd, J = 8.5, 1.5 Hz,1H), 7.40 (dd, J = 8.5, 4.4 Hz, 1H), 7.34 (dd, J = 8, 1.2 Hz, 1H), 7.07(dt, J = 8, 2 Hz, 1H), 7.00 (dt, J = 8, 2 Hz, 1H), 6.96 (dt, J = 8,2 Hz,1H), 6.78 (br t, 1H), 5.72 (br s, 2H), 4.95 (t, J = 6 Hz, 2H), 3.85 (q,J = 6 Hz, 2H), 3.42 (s, 2H), 2.89 (t, J = 7 Hz, 2H), 1.83 (quintet, J =7 H, # 2H), 1.50 (sextet, J = 7 Hz, 2H), 1.00 (t, J = 7 Hz, 3H) 193

(CDCl₃) δ 8.40 (dd, J = 4.4, 1.5 Hz, 1H), 8.07 (dd, J = 8.5, 1.5 Hz,1H), 7.43 (dd, J = 8.5, 4.5 Hz, 1H), 7.14 (d, J = 2 Hz, 1H), 7.06 (br t,1H), 6.98 (dd, J = 8, 2 Hz, 1H), 6.85 (d, J = 8 Hz, 1H), 5.75 (br s,2H), 4.96 (t, J = 6 Hz, 2H), 3.86 (q, J = 6 Hz, 2H), 3.31 (s, 2H), 2.89(t, J = 7 Hz, 2H), 1.89 (quintet, J = 7 Hz, 2H), 1.50 (sextet, # J = 7Hz, 2H), 1.00 (t, J = 7 Hz, 3H 194

(CDCl₃) δ 8.59 (dd, J = 4.5, 1.8 Hz, 1H), 8.09 (dd, J = 8.5, 1.8 Hz,1H), 7.47 (dd, J = 8.5, 4.5 Hz, 1H), 7.19 (bt, 1H), 5.79 (bs, 2H), 4.96(t, J = 6 Hz, 2H), 3.82 (q, J = 6 Hz, 2H), 3.36 (t, J = 6 Hz, 2H), 2.92(t, J = 7 Hz, 2H), 1.91 (q, J = 7 Hz, 2H), 1.87 (q, J = 7 Hz, 2H), 1.50(m, 6H), 1.01 (t, J = 7Hz, 3H) 195

(CDCl₃) δ 8.51 (dd, J = 4.5, 1.8 Hz, 1H), 8.07 (m, 3H), 7.42 (dd, J =4.5, 8.5), 1H), 7.31 (br t, 1H), 7.14 (d, J = 8 Hz, 2H), 5.8 (s, 2H),4.95 (t, J = 6 Hz, 2H), 4.257 (t, J = 7 Hz, 2H), 3.80 (q, J = 6 Hz, 2H),2.94 (t, J = 7 Hz, 2H), 1.90 (quintet, J = 7 Hz, 2H), 1.83 (quintet, J =7 Hz, 2H), 1.50 (sextet, J = 7 Hz, 2H), 1.34 # (quintet, J = 7 Hz, 2H),1.01 (t, J = 7 Hz, 3H) 196

(CDCl₃) δ 8.60 (dd, J = 4.5, 1.5 Hz, 1H), 8.11 (dd, J = 8.5, 1.5 Hz,1H), 7.49 (dd, J = 8.5, 4.5 Hz, 1H), 7.24 (br s, 1H), 6.0 (br s, 2H),4.95 (t, J = 6 Hz, 2H), 4.26 (t, J = 7 Hz, 2H), 3.82 (q, J = 6 Hz, 2H),2.93 (t, J = 7Hz, 2H), 1.91 (quintet, J = 7 Hz, 2H), 1.83 (m, 4H), 1.50(sextet, J = 7 Hz, 2H), 1.35 (quintet, J = 7 Hz, 2H), 1.05 # (m, 2H),1.01 (t, J = 7 Hz, 3H) 197

(CDCl₃) δ 8.60 (dd, J = 4.5, 1.5, 1H), 8.11 (dd, J = 8.5, 1.5, 1H), 7.49(dd, J = 8.5, 4.5 Hz, 1H), 7.01 (d, J = 8 Hz, 2H), 6.76 (d, J = 8 Hz,2H), 6.59 (br s, 1H), 5.69 (br s, 2H), 4.93 (t, J = 6 Hz, 2H), 3.80 (q,J = 6 Hz, 2H), 3.20 (s, 2H), 2.89 (t, J = 7 Hz, 2H), 2.44 (s, 3H), 1.90(quintet, J = 7 Hz, 2H), 1.51 (sextet, J = 7 Hz, 2H), 1.01 (t, J = 7 Hz,3H) 198

(CDCl₃) δ 8.58 (dd, J = 4.4, 1.5 Hz, 1H), 8.09 (dd, J = 8.3, 1.5 Hz,1H), 7.48 (dd, J = 8.3, 4.4 Hz, 1H), 7.30 (br t, 1H), 5.69 (br s, 2H);5.01 (m, 3H), 3.85 (q, J = 6 Hz, 2H), 2.92 (t, J = 7 Hz, 2H), 1.91(quintet, J = 7 Hz, 2H), 1.85 (m, 1H), 1.79 (m, 1H), 1.60 (m, 2H), 1.52(sextet, J = 7 Hz, 2H), 1.38 (d, J = 9 Hz, 1H), 1.27 (t, J = 6 Hz, 1H),# 1.00 (t, J = 7 Hz, 3H) 199

(CDCl₃) δ 8.59 (dd, J = 4.5, 1.5 Hz, 1H), 8.11 (dd, J = 8.5, 1.5 Hz,1H), 7.48 (dd, J = 8.5, 4.4 Hz, 1H), 7.48 (br s, 1H), 6.11 (br s, 2H),4.94 (t, J = 6 Hz, 2H), 3.83 (q, J = 6 Hz, 2H), 2.92 (t, J = 7 Hz, 2H),2.28 (m, 2H), 2.08 (t, J = 7 Hz, 2H), 1.90 (quintet, J = 7 Hz, 2H), 1.52(sextet, J = 7 Hz, 2H), 1.01 (t, J = 7 Hz, 3H) 200

(CDCl₃) δ 8.54 (dd, J = 4.4, 1.5 Hz, 1H), 8.10 (dd, J = 8.4, 1.5 Hz,1H), 7.46.(dd, J = 8.4, 4.4 Hz, 1H), 7.19 (br t, 1H), 7.12 (d, J = 8 Hz,2H), 6.88 (d, J = 8 Hz, 2H), 5.94 (br s, 2H), 4.91 (t, J = 6 Hz, 2H),3.78 (q, J = 6 Hz, 2H), 2.90 (t, J = 7 Hz, 2H), 2.65 (t, J = 7 Hz, 2H),2.12 (t, J = 7 Hz, 2H), 1.86 (quintet, J = 7 Hz, 2H), 1.52 (sextet, # J= 7 Hz, 2H), 1.02 (t, J = 7 Hz, 3H) 201

(CDCl₃) δ 8.60 (dd, J = 4.4, 1.5 Hz, 1H), 8.12 (dd, J = 8, 1.5 Hz, 1H),7.47 (dd, J = 8.0, 4.4 Hz, 1H), 6.86 (br s, 1H), 6.20 (br s, 2H), 4.96(t, J = 6 Hz, 2H), 3.81 (q, J = 6 Hz, 2H), 2.92 (t, J = 7 Hz, 2H), 1.90(m, 4H), 1.51 (sextet, J = 7 Hz, 2H), 1.33 (quintet, J = 7 Hz, 2H), 1.23(m, 16H), 1.01 (t, J = 7 Hz, 3H), 0.87 (t, J = 7 Hz, 3H) 202

(CDCl₃) δ 8.58 (dd, J = 4.3, 1.5 Hz, 1H), 8.04 (dd, J = 8.0, 1.5 Hz,1H), 7.56 (br s, 1H), 7.43 (dd, J = 8.0, 4.3 Hz, 1H), 5.84 (br s, 2H),4.94 (t, J = 6 Hz, 2H), 4.89 (br s, 1H), 3.85 (q, J = 6 Hz, 2H), 3.54(d, J = 6 Hz, 2H), 2.92 (t, J = 7 Hz, 2H), 1.89 (quintet, J = 7 Hz, 2H),1.51 (sextet, J = 7 Hz, 2H), 1.41 (s, 9H), 1.00 (t, J = 7 Hz, 3H) 203

(CDCl₃) δ 8.60 (d, J = 4.4 Hz, 1H), 8.07 (dd, J = 8.0, 1.5 Hz, 1H), 7.59(br s, 1H), 7.45 (dd, J = 8.5, 4.4 Hz, 1H), 5.88 (br s, 2H), 4.94 (m,2H), 4.77 (s, 1H), 3.93 (m, 1H), 3.84 (m. 2H), 2.94 (t, J = 7 Hz, 2H),1.89 (quintet, J = 7 Hz, 2H), 1.52 (sextet, J = 7 Hz, 2H), 1.40 (s, 9H),1.01 (d, J = 7 Hz, 3H), 0.99 (t, J = 7 Hz, 3H) 204

(d₆-DMSO at 80° C.) δ 8.53 (dd, J = 4.4, 1.5 Hz, 1H), 8.53 (t, J = 6 Hz,1H), 7.96 (dd, J = 8.3, 1.5 Hz, 1H), 7.45 (dd, J = 8.3, 4.4 Hz, 1H),7.32 (d, J = 4 Hz, 1H), 7.16 (d, J = 4 Hz, 1H), 6.81 (br s, 2H), 4.91(t, J = 6 Hz, 2H), 3.78 (q, J = 6 Hz, 2H), 2.85 (t, J = 7 Hz, 2H), 1.77(quintet, J = 7 Hz, 2H), 1.37 (sextet, J = 7 Hz, 2H), 0.87 (t, J = 7 Hz,3H) 205

(CDCl₃) δ 9.16 (d, J = 1.4 Hz, 1H), 8.66 (dd, J = 4.4, 1.5 Hz, 1H), 8.44(t, J = 6 Hz, 1H), 8.11 (d, J = 1.4 Hz, 1H), 8.09 (dd, J = 8.4, 1.5 Hz,1H), 7.47 (dd, J = 8.5, 4.4 Hz, 1H), 6.10 (br s, 2H), 5.11 (t, J = 6 Hz,2H), 4.05 (q, J = 6 Hz, 2H), 2.92 (t, J = 7 Hz, 2H), 2.59 (s, 3H), 1.87(quintet, J = 7 Hz, 2H), 1.46 (sextet, J = 7 Hz, 2H), 0.95 (t, J = 7 Hz,3H) 206

(CDCl₃) δ 8.73 (dd, J = 4.4, 1.5 Hz, 1H), 8.12 (dd, J = 8.4, 1.5 Hz,1H), 7.95 (br s, 1H), 7.52 (dd, J = 8.4, 4.4 Hz, 1H), 6.91 (d, J = 3.4Hz, 1H), 6.31 (d, J = 3.4 Hz, 1H), 6.04 (br s, 2H), 5.07 (t, J = 6 Hz,2H), 3.99 (q, J = 6 Hz, 2H), 2.93 (t, J = 7 Hz, 2H), 1.91 (quintet, J =7 Hz, 2H), 1.50 (sextet, J = 7 Hz, 2H), 0.99 (t, J = 7 Hz, 3H) 207

(CDCl₃) δ 8.50 (dd, J = 4.4, 1.5 Hz, 1H), 8.42 (d, J = 4 Hz, 1H), 8.19(d, J = 1.5 Hz, 1H), 8.09 (dd, J = 8.2, 1.5 Hz, 1H), 7.47 (dd, J = 8.3,4.4 Hz, 1H), 7.26 (br s, 1H), 7.23 (d, J = 8 Hz, 1H), 7.07 (dd, J = 8.5,5 Hz, 1H), 6.06 (br s, 2H), 3.95 (t, J = 6 Hz, 2H), 3.84 (q, J = 6 Hz,2H), 3.21 (s, 2H), 2.87 (t, J = 7 Hz, 2H), 1.88 (quintet, # J = 7 Hz,2H), 1.50 (sextet, J = 7 Hz, 2H), 1.00 (t, J = 7 Hz, 3H) 208

(CDCl₃) δ 8.54 (dd, J = 4.4, 1.5 Hz, 1H), 8.37 (d, J = 4Hz, 1H), 8.24(br s, 1H), 8.09 (dd, J = 8.5, 1.5 Hz, 1H), 7.46 (dd, J = 8.5, 4.4 Hz,1H), 7.35 (br t, 1H), 7.27 (td, J = 8, 2 Hz, 1H), 7.08 (dd, J = 8, 5 Hz,1H), 5.98 (br s, 2H), 4.91 (t, J = 6 Hz, 2H), 3.79 (q, J = 6 Hz, 2H),2.90 (t, J = 7 Hz, 2H), 2.69 (t, J = 7 Hz, 2H), 2.14 (t, J = 7 Hz, 2H),1.90 # (quintet, J = 7 Hz, 2H), 1.52 (sextet, J = 7 Hz, 2H), 1.01 (t, J= 7 Hz, 3H) 209

(d₆-DMSO) δ 8.52 (d, J = 8.3 Hz, 1H), 8.37 (m, 2H), 7.96 (d, J = 8.3 Hz,1H), 7.48 (dd, J = 8.3, 4.5 Hz, 1H), 7.14 (br s, 2H), 4.72 (t, J = 6 Hz,2H), 4.12 (t, J = 6 Hz, 2H), 3.56 (q, J = 6 Hz, 2H), 2.81 (t, J = 7 Hz,2H), 2.52 (m, 2H), 2.33 (s, 3H), 1.75 (quintet, J = 7 Hz, 2H), 1.40(sextet, J = 7 Hz, 2H), 0.94 (t, J = 7 Hz, 3H 210

(CDCl₃) δ 8.52 (dd, J = 4.4, 1.5 Hz, 1H), 8.05 (dd, J = 8.4, 1.5 Hz,1H), 7.76 (t, J = 6 Hz, 1H), 7.43 (dd, J = 8.5, 4.4 Hz, 1H), 7.27 (d, J= 8 Hz, 2H), 7.06 (d, J = 8 Hz, 2H), 5.82 (br s, 2H), 5.06 & 4.83 (m,2H), 3.88 & 3.79 (m, 2H), 3.03 (m, 1H), 2.89 (t, J = 7 Hz, 2H), 2.79 (m,1H), 2.5 (m, 3H), 2.25 (m, 1H), 1.90 (quintet, J = 7 Hz, 2H), # 1.51(sextet, J = 7 Hz, 2H), 1.00 (t, J = 7 Hz, 3H) 211

(d₆-DMSO) δ 8.53 (dd, J = 4.4, 1.5 Hz, 1H), 8.24 (t, J = 6 Hz, 1H), 7.96(dd, J = 8.4, 1.5 Hz, 1H), 7.84 (m, 4H), 7.48 (dd, J = 4.4, 8.4 Hz, 1H),7.18 (br s, 2H), 4.75 (t, J = 6 Hz, 2H), 3.73 (t, J = 7 Hz, 2H), 3.52(q, J = 6 Hz, 2H), 2.86 (t, J = 7 Hz, 2H), 2.34 (t, J = 7 Hz, 2H), 1.79(quintet, J = 7 Hz, 2H), 1.40 (sextet, J = 7 Hz, 2H), 0.92 (t, J = 7 Hz,3H) 212

(CDCl₃) δ 8.60 (dd, J = 4.4, 1.5 Hz, 1H), 8.04 (dd, J = 8.5, 1.5 Hz,1H), 7.68 (dd, J = 3.5, 1.2 Hz, 1H), 7.61 (dd, J = 3.5, 1.2 Hz, 1H),7.43 (dd, J = 8.5, 4.4 Hz, 1H), 7.39 (t, J = 6 Hz, 1H), 7.10 (dd, J = 5,3.5 Hz, 1H), 5.79 (br s, 2H), 4.93 (t, J = 6 Hz, 2H), 3.82 (q, J = 6 Hz,2H), 3.12 (t, J = 7 Hz, 2H), 2.92 (t, J = 7 Hz, 2H), 2.32 (t, J = 7 Hz,2H), # 1.89 (quintet, J = 7 Hz, 2H), 1.49 (sextet, J = 7 Hz, 2H), 0.99(t, J = 7 Hz, 3H)

EXAMPLE 213 Compound of formula IIN-[2-(4-Amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-5-oxo-2-pyrrolinecarboxamide

[0455]

[0456] Using the general method of Example 97 L-pyroglutamic acid (0.23g, 1.7 mmole) was reacted with2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethaneamine(0.5 g, 1.7 mmole) to provide 0.10 g ofN-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)ethyl]-5-oxo-2-pyrrolinecarboxamideas a white powder, m.p. 135-138° C. Analysis: Calculated forC₂₀H₂₅N₇O₂½CH₃CN: % C, 60.63; % H, 6.42; % N, 25.25; Found: % C, 60.14;% H, 6.41; % N, 25.20. HRMS (EI) calcd for C₂₀H₂₅N₇O₂ (M⁺) 396.2103found 396.2112

Test Methods Cytokine Induction in Human Cells

[0457] An in vitro human blood cell system was used to assess cytokineinduction by compounds of the invention. Activity is based on themeasurement of interferon and tumor necrosis factor (ℑ) (IFN and TNF,respectively) secreted into culture media as described by Testerman et.al. In “Cytokine Induction by the Immunomodulators Imiquimod andS-27609”, Journal of Leukocyte Biology, 58, 365-372 (September, 1995).

[0458] Blood Cell Preparation for Culture

[0459] Whole blood is collected by venipuncture into EDTA vacutainertubes from healthy human donors. Peripheral blood mononuclear cells(PBMCs) are separated from whole blood by Histopaque®-1077 (SigmaChemicals, St. Louis, Mo.) density gradient centrifugation. The PBMCsare suspended at 1.5-2×10⁶ cells/mL in RPMI 1640 medium containing 10%fetal bovine serum, 2 mM L-glutamine and 1% penicillin/streptomycinsolution (RPMI complete). 1 mL portions of PBMC suspension are added to24 well flat bottom sterile tissue culture plates.

[0460] Compound Preparation

[0461] The compounds are solubilized in dimethyl sulfoxide (DMSO). TheDMSO concentration should not exceed a final concentration of 1% foraddition to the culture wells. The compounds are generally tested in aconcentration range of from 0.1 to 100 μM.

[0462] Incubation

[0463] The solution of test compound is added to the wells containing 1mL of PBMCs in media. The plates are covered with plastic lids, mixedgently and then incubated for 18 to 24 hours at 37° C. with a 5% carbondioxide atmosphere.

[0464] Separation

[0465] Following incubation the plates are centrifuged for 5-10 minutesat 1000 rpm (200×g) at 4° C. The cell culture supernatant is removedwith a sterile polypropylene pipet and transferred to a 2 mL sterilecryotube. Samples are maintained at −70° C. until analysis.

Interferon Analysis/Calculation

[0466] Interferon is determined by bioassay using A549 human lungcarcinoma cells challenged with encephalomyocarditis. The details of thebioassay method have been described by G. L. Brennan and L. H.Kronenberg in “Automated Bioassay of Interferons in Micro-test Plates”,Biotechniques, June/July, 78, 1983, incorporated herein by reference.Briefly stated the method is as follows: A549 cells are incubated withsamples and standard interferon dilutions at 37° C. for 24 hours. Theincubated cells are then infected with an inoculum ofencephalomyocarditis virus. The infected cells are incubated for anadditional 24 hours at 37° C. before quantifying for viral cytopathiceffect. The viral cytopathic effect is quantified by staining followedby visual scoring of the plates. Results are expressed as alphareference units/mL based on the value obtained for NIH Human LeukocyteIFN standard.

Tumor Necrosis Factor (ℑ) Analysis

[0467] Tumor necrosis factor (ℑ) (TNF) concentration is determined usingan ELISA kit available from Genzyme, Cambridge, Mass. The results areexpressed as pg/mL.

[0468] In the table below, a “+” indicates that the compound induced theindicated cytokine at that particular concentration, a “−” indicatesthat the compound did not induce the indicated cytokine at thatparticular concentration, and a “±” indicates that the results wereequivocal at that particular concentration. Cytokine Induction in HumanCells IFN TNF Dose Concentration (μM) Dose Concentration (μM) Example0.1 1.0 10.0 100.0 0.1 1.0 10.0 100.0 9 ± − + − − − − − 10 + + + + − −− + 12 Not run + + + Not run + + + 13 Not run + + + Not run + + + 22 Notrun − − − Not run − ± + 23 Not run + + − Not run − ± − 25 Not run − + +Not run − ± − 26 Not run + − + Not run + ± − 27 Not run + + + Notrun + + + 28 Not run + + + Not run − + + 32 Not run + + + Not run − − −33 Not run + + + Not run − − − 36 Not run + + + Not run − + − 39 Notrun + + − Not run + + − 40 Not run + + ± Not run + + + 45 + + + − − + +− 46 + + + + + + + + 46 Not run + + ± Not run + + + 47 − + + ± − + + +48 + + + − − + + − 49 + + + + − + + + 50 Not run + + − Not run + + − 51Not run + + + Not run + + − 52 Not run + + − Not run + + − 53 + + + +− + + − 54 Not run + + + Not run + + + 55 Not run + + + Not run + + − 56− + + − − − + − 57 − + + + − − + + 58 + + + − − + + − 62 + + + + + + + +65 + + + + − + + + 70 + + + − − + + − 75 − + + + − − + − 80 − + + − −− + − 85 + + + − − + + − 90 ± + + + − − + + 91 + + + + + + + + 92± + + + − + + + 93 − + + + − + + + 94 − + + + − + + + 95 ± + + + − − + +96 − ± + + − − + + 97 − − + + − − + + 98 − + + + − + + + 99 − − + + −− + + 100 − − + + − − + + 101 − − + + − − + + 101 − − + + − − − +102 + + + + + + + + 103 − − + + − − + + 104 − + + − − − + − 105 + + + +− − + + 106 + + + − − + + − 107 + + + − − + + − 108 + + + + ± − + +109 + + + + − ± + + 110 + + + + − + + + 111 − − + + − − + + 112 + + +± + + − − 113 − + + + − + + + 114 − − + + − − + + 115 − − + + − − + +116 − + + + − + + + 117 − − + + − − + + 118 Not run − + + Not run − + +119 Not run − − − Not run − − − 120 Not run + + + Not run − + + 121 Notrun + + + Not run + + + 122 Not run − + + Not run − + + 123 Not run ± −− Not run − ± − 124 Not run + + + Not run − + + 125 Not run + + + Notrun − + + 126 Not run + + + Not run − + + 127 Not run + + + Not run− + + 128 Not run ± + + Not run − ± + 129 Not run + + + Not run + + +130 Not run + + + Not run + + + 131 Not run + + + Not run + + + 132 Notrun + + + Not run + + + 133 Not run + + + Not run + + + 134 Notrun + + + Not run + + + 135 Not run − + + Not run − + + 136 Notrun + + + Not run − + + 137 Not run + + + Not run − ± + 138 Notrun + + + Not run + + + 139 Not run + + + Not run − + + 140 Notrun + + + Not run + + + 141 Not run + + + Not run − + + 142 Notrun + + + Not run − + + 143 Not run − + + Not run − ± − 144 + + + +− + + + 145 − − + + − + + + 146 + + + − + + + + 147 − + + + − − + + 148− + + + − − + + 149 − − − − − − − − 150 − − + + − − + + 151 − − + + −− + + 152 − − + + − − + + 153 − + + − − + + − 155 − + + + − − + +156 + + + + − + + − 157 + + + − − − + − 158 − + + + − − + − 159 + + +− + + + + 160 + + + − − + + − 161 ± + + + − − + + 162 + + + + − + + +163 + + + + − + + − 164 + + + − − + + − 165 + + + + − + + + 166 − + + −− + + − 167 − + + − − − + − 168 − + + + − + + − 169 − + + + − − + + 170− + + + − − + + 171 + + + ± − + + − 172 + + + + − + + + 173 + + + +− + + + 174 + + + + + + + − 175 − + + − − + + − 176 − + + + − − + + 177− − + − − − + − 178 + + + + + − + − 179 − + + + − + + − 180 + + + +± + + + 181 − − ± + − − − + 182 − + + + − + + − 183 − − − − − − − −183 + + + − 184 + + + − + + + − 185 − + + ± − ± + − 186 + + + + − + + +187 − + + + − + + − 188 + + + − − + + − 189 − + + − − ± + − 190 + + + −− + + − 191 Not run + + + Not run − + + 192 − − + + − − + + 193 − − + +− − + + 194 − + + + − + + + 195 − − + − − + + + 196 − − + + − − + + 197− − + + − + + + 198 − − + + − + + + 199 + − + + − − + + 200 − − + + −− + + 201 − − − − − − − + 202 − − + + − − + + 203 − − + + − − + +204 + + + + − + + + 205 + + + + − + + + 206 + + + + − + + + 207 − − + +− − + + 208 − − + + − − − − 208 − ± + + 209 − − + + − − + + 210 −− + + + + + + 211 − − + + − − + + 212 − + + + − + + +

Interferon (α) Induction in Human Cells

[0469] An in vitro human blood cell system was used to assess interferoninduction by compounds of the invention. Activity is based on themeasurement of interferon secreted into culture media. Interferon ismeasured by bioassay.

[0470] Blood Cell Preparation for Culture

[0471] Whole blood was collected by venipuncture into EDTA vacutainertubes. Peripheral blood mononuclear cells (PBM's) were separated fromwhole blood by using either LeucoPREP™ Brand Cell Separation Tubes(available from Becton Dickinson) or Ficoll-Paque® solution (availablefrom Pharmacia LKB Biotechnology Inc, Piscataway, N.J.). The PBM's weresuspended at 1×10⁶/mL in RPMI 1640 media (available from GIBCO, GrandIsland, N.Y.) containing 25 mM HEPES(N-2-hydroxyethylpiperazine-N′-2-ethanesulfonic acid) and L-glutamine(1% penicillin-streptomycin solution added) with 10% heat inactivated(56° C. for 30 minutes) autologous serum added. 200 SAL portions of PBMsuspension were added to 96 well (flat bottom) MicroTest III steriletissue culture plates.

[0472] Compound Preparation

[0473] The compounds were solubilized in ethanol, dimethyl sulfoxide ortissue culture water then diluted with tissue culture water, 0.01Nsodium hydroxide or 0.01N hydrochloric acid (The choice of solvent willdepend on the chemical characteristics of the compound being tested.).Ethanol or DMSO concentration should not exceed a final concentration of1% for addition to the culture wells. Compounds were initially tested ina concentration range of from about 0.1 μg/mL to about 5 μg/mL.Compounds which show induction at a concentration of 0.5 μg/mL were thentested in a wider concentration range.

[0474] Incubation

[0475] The solution of test compound was added in a volume (less than orequal to 50 μL) to the wells containing 200 μL of diluted whole blood orof PBM's in media. Solvent and/or media was added to control wells(wells with no test compound) and as needed to adjust the final volumeof each well to 250 μL. The plates were covered with plastic lids,vortexed gently and then incubated for 48 hours at 37° C. with a 5%carbon dioxide atmosphere.

[0476] Separation

[0477] Following incubation, the plates were covered with parafilm andthen centrifuged at 1000 rpm for 10 to 15 minutes at 4° C. in a Damon ECModel CRU-5000 centrifuge. Media (about 200 mL) was removed from 4 to 8wells and pooled into 2 mL sterile freezing vials. Samples weremaintained at −70° C. until analysis.

[0478] Interferon Analysis/Calculation

[0479] Interferon was determined by bioassay using A549 human lungcarcinoma cells challenged with encephalomyocarditis. The details of thebioassay method have been described by G. L. Brennan and L. H.Kronenberg in “Automated Bioassay of Interferons in Micro-test Plates”,Biotechniques, June/July, 78, 1983, incorporated herein by reference.Briefly stated the method is as follows: interferon dilutions and A549cells are incubated at 37° C. for 12 to 24 hours. The incubated cellsare infected with an inoculum of encephalomyocarditis virus. Theinfected cells are incubated for an additional period at 37° C. beforequantifying for viral cytopathic effect. The viral cytopathic effect isquantified by staining followed by spectrophotometric absorbancemeasurements. Results are expressed as alpha reference units/mL based onthe value obtained for NIH HU IF-L standard. The interferon wasidentified as essentially all interferon alpha by testing incheckerboard neutralization assays against rabbit anti-human interferon(beta) and goat anti-human interferon (alpha) using A549 cell monolayerschallenged with encephalomyocarditis virus.

[0480] In the table below, a “+” indicates that the compound inducedinterferon α at that particular concentration, a “−” indicates that thecompound did not induce interferon α at that particular concentration,and a “±” indicates that the results were equivocal at that particularconcentration. Interferon (α) Induction in Human Cells DoseConcentration (μg/mL) Example 0.01 0.05 0.10 0.50 1.0 5.0 10.0 25.0 50.09 − − − − − − − − − 10 − − − − + + + + + 12 − − + + + + + + + 13− + + + + + + + + 22 not not not not − − − + not run run run run run 23not not not not − − − − not run run run run run 25 − − − − − + + + notrun 26 − − − − − ± + + not run 27 − − + + + + + + not run 28 −± + + + + + + not run 32 − − − − + + + + + 33 − − − − − + + + + 36− + + + + + + + + 39 − − + + + + + + + 40 − + + + + + + + +

[0481] The present invention has been described with reference toseveral embodiments thereof. The foregoing detailed description andexamples have been provided for clarity of understanding only, and nounnecessary limitations are to be understood therefrom. It will beapparent to those skilled in the art that many changes can be made tothe described embodiments without departing from the spirit and scope ofthe invention. Thus, the scope of the invention should not be limited tothe exact details of the compositions and structures described herein,but rather by the language of the claims that follow.

1-20 (canceled)
 21. A compound of formula

wherein A is —N═CR—CR═CR—; —CR═N—CR═CR—: —CR═CR—N═CR—: or —CR═CR—CR═N—;R₁ is selected from the group consisting of: hydrogen; C₁₋₂₀ alkyl orC₂₋₂₀ alkenyl that is unsubstituted or substituted by one or moresubstituents selected from the group consisting of: aryl; heteroaryl;heterocyclyl; O—C₁₋₂₀ alkyl, O—(C₁₋₂₀ alkyl)₀₋₁-aryl; O—(C₁₋₂₀alkyl)₀₋₁-heteroaryl; O—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl; C₁₋₂₀alkoxycarbonyl; S(O)₀₋₂—C₁₋₂₀ alkyl; S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-aryl;S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl; S(O)₀₋₂—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl; N(R₃)₂; N₃; oxo; halogen; NO₂; OH; and SH; andC₁₋₂₀ alkyl-NR₃-Q-X—R₄ or —C₂₋₂₀ alkenyl-NR₃-Q-X—R₄ wherein Q is —CO— or—SO₂—; X is a bond, —O— or —NR₃— and R₄ is aryl; heteroaryl;heterocyclyl; or —C₁₋₂₀ alkyl or C₂₋₂₀ alkenyl that is unsubstituted orsubstituted by one or more substituents selected from the groupconsisting of: aryl; heteroaryl; heterocyclyl; O—C₁₋₂₀ alkyl, O—(C₁₋₂₀alkyl)₀₋₁-aryl; O—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl; O—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl; C₁₋₂₀ alkoxycarbonyl; S(O)₀₋₂—C₁₋₂₀ alkyl;S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-aryl; S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl;S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl; N(R₃)₂; NR₃—CO—O—C₁₋₂₀alkyl; N₃;oxo; halogen; NO₂; OH; and SH; or R₄ is

wherein Y is —N— or —CR—; R₂ is selected from the group consisting of:hydrogen; C₁₋₁₀ alkyl; C₂₋₁₀ alkenyl; aryl C₁₋₁₀ alkyl —O—C₁₋₁₀-alkyl;C₁₋₁₀ alkyl-O—C₂₋₁₀ alkenyl; and C₁₋₁₀ alkyl or C₂₋₁₀ alkenylsubstituted by one or more substituents selected from the groupconsisting of: OH; halogen; N(R₃)₂; CO—N(R₃)₂; CO—C₁₋₁₀ alkyl; N₃; aryl;heteroaryl; heterocyclyl; CO-aryl; and CO-heteroaryl; each R₃ isindependently selected from the group consisting of hydrogen and C₁₋₁₀alkyl; and each R is independently selected from the group consisting ofhydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, halogen and trifluoromethyl, or apharmaceutically acceptable salt thereof.
 22. A compound of formula

wherein R₁ is selected from the group consisting of: hydrogen; C₁₋₂₀alkyl or C₂₋₂₀ alkenyl that is unsubstituted or substituted by one ormore substituents selected from the group consisting of: aryl;heteroaryl; heterocyclyl; O—C₁₋₂₀ alkyl, O—(C₁₋₂₀ alkyl)₀₋₁-aryl;O—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl; O—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl; C₁₋₂₀alkoxycarbonyl; S(O)₀₋₂—C₁₋₂₀ alkyl; S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-aryl;S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl; S(O)₀₋₂—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl; N(R₃)₂; N₃; oxo; halogen; NO₂; OH; and SH; andC₁₋₂₀ alkyl-NR₃-Q-X—R₄ or —C₂₋₂₀ alkenyl-NR₃-Q-X—R₄ wherein Q is —CO— or—SO₂—; X is a bond, —O— or —NR₃— and R₄ is aryl; heteroaryl;heterocyclyl; or —C₁₋₂₀ alkyl or C₂₋₂₀ alkenyl that is unsubstituted orsubstituted by one or more substituents selected from the groupconsisting of: aryl; heteroaryl; heterocyclyl; O—C₁₋₂₀ alkyl, —O—(C₁₋₂₀alkyl)₀₋₁-aryl; O—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl; O—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl; C₁₋₂₀ alkoxycarbonyl; S(O)₀₋₂—C₁₋₂₀ alkyl;S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-aryl; S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl;S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl; N(R₃)₂; NR₃—CO—O—C₁₋₂₀alkyl; N₃;oxo; halogen; NO₂; OH; and SH; or R₄ is

wherein Y is —N— or —CR—; R₂ is selected from the group consisting of:hydrogen; C₁₋₁₀ alkyl; C₂₋₁₀ alkenyl; aryl; C₁₋₁₀ alkyl-O—C₁₋₁₀-alkyl;C₁₋₁₀ alkyl-O—C₂₋₁₀ alkenyl; and C₁₋₁₀ alkyl or C₂₋₁₀ alkenylsubstituted by one or more substituents selected from the groupconsisting of: OH; halogen; N(R₃)₂; CO—N(R₃)₂; CO—C₁₋₁₀ alkyl; N₃; aryl;heteroaryl; heterocyclyl; CO-aryl; and CO-heteroaryl; each R₃ isindependently selected from the group consisting of hydrogen and C₁₋₁₀alkyl; and each R is independently selected from the group consisting ofhydrogen, C₁₋₁₀ alkyl C₁₋₁₀ alkoxy, halogen and trifluoromethyl, or apharmaceutically acceptable salt thereof.
 23. A compound of formula

wherein R₁ is selected from the group consisting of: hydrogen; C₁₋₂₀alkyl or C₂₋₂₀ alkenyl that is unsubstituted or substituted by one ormore substituents selected from the group consisting of: aryl;heteroaryl; heterocyclyl; O—C₁₋₂₀ alkyl, O—(C₁₋₂₀ alkyl)₀₋₁-aryl;O—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl; O—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl; C₁₋₂₀alkoxycarbonyl; S(O)₀₋₂—C₁₋₂₀ alkyl; S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-aryl;S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl; S(O)₀₋₂—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl; N(R₃)₂; N₃; oxo; halogen; NO₂; OH; and SH; andC₁₋₂₀ alkyl-NR₃-Q-X—R₄ or —C₂₋₂₀ alkenyl-NR₃-Q-X—R₄ wherein Q is —CO— or—SO₂—; X is a bond, —O— or —NR₃— and R₄ is aryl; heteroaryl;heterocyclyl; or —C₁₋₂₀ alkyl or C₂₋₂₀ alkenyl that is unsubstituted orsubstituted by one or more substituents selected from the groupconsisting of: aryl; heteroaryl; heterocyclyl; O—C₁₋₂₀ alkyl, O—(C₁₋₂₀alkyl)₀₋₁-aryl; O—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl; O—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl; C₁₋₂₀ alkoxycarbonyl; S(O)₀₋₂—C₁₋₂₀ alkyl;S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-aryl; S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl;S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl; N(R₃)₂; NR₃—CO—O—C₁₋₂₀alkyl; N₃;oxo; halogen; NO₂; OH; and SH; or R₄ is

wherein Y is —N— or —CR—; R₂ is selected from the group consisting of:hydrogen; C₁₋₁₀ alkyl; C₂₋₁₀ alkenyl; aryl; C₁₋₁₀ alkyl-O—C₁₋₁₀-alkyl;C₁₋₁₀ alkyl-O—C₂₋₁₀ alkenyl; and C₁₋₁₀ alkyl or C₂₋₁₀ alkenylsubstituted by one or more substituents selected from the groupconsisting of: OH; halogen; N(R₃)₂; CO—N(R₃)₂; CO—C₁₋₁₀ alkyl; N₃; aryl;heteroaryl; heterocyclyl; CO-aryl; and CO-heteroaryl; each R₃ isindependently selected from the group consisting of hydrogen and C₁₋₁₀alkyl; and each R is independently selected from the group consisting ofhydrogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, halogen and trifluoromethyl, or apharmaceutically acceptable salt thereof.
 24. A compound of formula

wherein A is ═N—CR═CR—CR═; ═CR—N═CR—CR═; ═CR—CR═N—CR═; or ═CR—CR═CR—N═;R₇ is OH, halogen, or NHR₁, R₁ is selected from the group consisting of:hydrogen; C₁₋₂₀ alkyl or C₂₋₂₀ alkenyl that is unsubstituted orsubstituted by one or more substituents selected from the groupconsisting of: aryl; heteroaryl; heterocyclyl; O—C₁₋₂₀ alkyl, O—(C₁₋₂₀alkyl)₀₋₁-aryl; O—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl; O—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl; C₁₋₂₀ alkoxycarbonyl; S(O)₀₋₂—C₁₋₂₀ alkyl;S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-aryl; S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl;S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl; N(R₃)₂; N₃; oxo; halogen; NO₂;OH; and SH; and C₁₋₂₀ alkyl-NR₃-Q-X—R₄ or —C₂₋₂₀ alkenyl-NR₃-Q-X—R₄wherein Q is —CO— or —SO₂—; X is a bond, —O— or —NR₃— and R₄ is aryl;heteroaryl; heterocyclyl; or —C₁₋₂₀ alkyl or C₂₋₂₀ alkenyl that isunsubstituted or substituted by one or more substituents selected fromthe group consisting of: aryl; heteroaryl; heterocyclyl; O—C₁₋₂₀ alkyl,O—(C₁₋₂₀ alkyl)₀₋₁-aryl; O—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl; O—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl; C₁₋₂₀ alkoxycarbonyl; S(O)₀₋₂—C₁₋₂₀ alkyl;S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-aryl; S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl;S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl; N(R₃)₂; NR₃—CO—O—C₁₋₂₀alkyl; N₃;oxo; halogen; NO₂; OH; and SH; or R₄ is

wherein Y is —N— or —CR—; R₈ is H, NO₂ or NH₂; each R is independentlyselected from the group consisting of hydrogen and C₁₋₁₀ alkyl and eachR is independently selected from the group consisting of hydrogen, C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, halogen and trifluoromethyl; or a pharmaceuticallyacceptable salt thereof.
 25. A compound of formula

wherein A is ═N—CR═CR—CR═; ═CR—N═CR—CR═; ═CR—CR═N—CR═; or ═CR—CR═CR—N═;each R is independently selected from the group consisting of hydrogen.C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, halogen and trifluoromethyl; and R₉ is H orC₁₋₁₀ alkyl. 26 A compound of formula

wherein R₁ is selected from the group consisting of: C₁₋₂₀ alkyl orC₂₋₂₀ alkenyl that is unsubstituted or substituted by one or moresubstituents selected from the group consisting of: aryl; heteroaryl;heterocyclyl; O—C₁₋₂₀ alkyl; O—(C₁₋₂₀ alkyl)₀₋₁-aryl; O—(C₁₋₂₀alkyl)₀₋₁-heteroaryl; O—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl; C₁₋₂₀alkoxycarbonyl; S(O)₀₋₂—C₁₋₂₀ alkyl; S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-aryl;S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl; S(O)₀₋₂—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl; N(R₃)₂; N₃; oxo; halogen; NO₂; OH; and SH; andC₁₋₂₀ alkyl-NR₃-Q-X—R₄ or —C₂₋₂₀ alkenyl-NR₃-Q-X—R₄ wherein Q is —CO— or—SO₂—; X is a bond, —O— or —NR₃— and R₄ is aryl; heteroaryl;heterocyclyl; or —C₁₋₂₀ alkyl or C₂₋₂₀ alkenyl that is unsubstituted orsubstituted by one or more substituents selected from the groupconsisting of: aryl; heteroaryl; heterocyclyl; O—C₁₋₂₀ alkyl; O—(C₁₋₂₀alkyl)₀₋₁-aryl; O—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl; O—(C₁₋₂₀alkyl)₀₋₁-heterocyclyl; C₁₋₂₀ alkoxycarbonyl; S(O)₀₋₂—C₁₋₂₀ alkyl;S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-aryl; S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heteroaryl;S(O)₀₋₂—(C₁₋₂₀ alkyl)₀₋₁-heterocyclyl; N(R₃)₂; NR₃—CO—O—C₁₋₂₀alkyl; N₃;